Cdk2 inhibitors and methods of using the same

ABSTRACT

The present disclosure relates generally to Cyclin-dependent kinase 2 (CDK2) inhibiting chemical compounds and uses thereof in the inhibition of the activity of CDK2. The disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed herein and methods of using said compounds and compositions in the treatment of various disorders related to CDK2 activity.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.63/202,844, filed Jun. 26, 2021, which is hereby incorporated byreference in its entirety.

FIELD

The present disclosure relates generally to Cyclin-dependent kinase 2(CDK2) inhibiting chemical compounds and uses thereof in the inhibitionof the activity of CDK2. The disclosure also provides pharmaceuticallyacceptable compositions comprising compounds disclosed herein andmethods of using said compounds and compositions in the treatment ofvarious disorders related to CDK2 activity.

BACKGROUND

Cell cycle dysregulation, including uncontrolled cell growth, impairedcell differentiation and abnormal apoptosis have been shown to be causedby over activity of Cyclin-dependent kinases (CDKs). CDKs are importantserine/threonine protein kinases that become active when combined with aspecific cyclin partner. There are various subtypes of CDKs, each havinga different role during the cell cycle, with varying levels of activityduring each of the phases. CDK1, CDK2, CDK4 and CDK6 have been found tobe specifically important subtypes, where over activity of one or moreof these subtypes may lead to dysregulation of the cell cycle and thedevelopment of a variety of cancers. The S phase of the cell cycle isresponsible for DNA replication and is the phase where aberrant DNAreplication may occur. The CDK2/cyclin E complex is required for thecell cycle transition from the G1 phase to the S phase and theCDK2/cyclin A complex is required for the cell cycle transition from theS phase to the G2 phase. Therefore, selective inhibition of theCDK2/cyclin E and/or CDK2/cyclin A complexes can prevent aberrant DNAreplication and can be used to treat certain cancers.

Accordingly, there is a need for the development of compounds capable ofinhibiting the activity of CDK2/cyclin complexes, and pharmaceuticalcompositions thereof, for the prevention, and treatment of CDK2 relateddiseases or disorders.

SUMMARY

The present disclosure is based at least in part on the identificationof compounds that bind and inhibit Cyclin-dependent kinase 2 (CDK2) andmethods of using the same to treat diseases associated with CDK2activity. Disclosed herein is a compound according to Formula I or apharmaceutically acceptable salt thereof:

wherein each variable is as defined and described herein.

Compounds of the present disclosure, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with CDK2 activity. Such diseases,disorders, or conditions include those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Disclosure:

The present disclosure provides compounds capable of inhibitingCyclin-dependent kinase 2 (CDK2) and/or CDK2/cyclin complexes.

In some embodiments, provided herein are compounds according to FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:

R^(A) is

L¹ is a covalent bond or a saturated or unsaturated, straight orbranched, optionally substituted bivalent C₁₋₆ hydrocarbon chain,wherein 0-2 methylene units of L¹ are independently replaced by —O—,—NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—,—S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—;

R¹ is hydrogen, an optionally substituted C₁₋₆ aliphatic group, or anoptionally substituted cyclic group selected from a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring, a 7-12membered saturated or partially unsaturated bicyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur);

R² is hydrogen, an optionally substituted C₁₋₆ aliphatic group, —C(O)OR,—C(O)NR₂, or an optionally substituted cyclic group selected from phenyland a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur);

each instance of R³ is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group;

R⁴ is a cyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 7-12 membered saturated orpartially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁵;

each instance of R⁵ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, an optionally substitutedC₁₋₆ aliphatic group, or an optionally substituted —C₁₋₆ aliphatic-Cygroup;

L² is a saturated or unsaturated, straight or branched, optionallysubstituted bivalent C₁₋₄ hydrocarbon chain, wherein 0-2 methylene unitsof L² are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—;

R⁶ is an optionally substituted C₁₋₆ aliphatic group, or a cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 7-12 membered saturated or partiallyunsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),and an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),wherein the cyclic group is optionally substituted with one or moreinstances of R⁷;

each instance of R⁷ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(O)S(O)₂R, —N(R)C(NR)NR₂, —N(R)S(O)₂N R₂, —N(R)S(O)₂R, anoptionally substituted C₁₋₆ aliphatic group, or Cy, or two instances ofR⁶ on the same carbon atom are taken together to form an oxo group;

L³ is a saturated or unsaturated, straight or branched, optionallysubstituted bivalent C₁₋₄ hydrocarbon chain, wherein 0-2 methylene unitsof L³ are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—;

R⁸ is a cyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 7-12 membered saturated orpartially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁹;

each instance of R⁹ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, an optionally substitutedC₁₋₆ aliphatic group, an optionally substituted C₁₋₆ aliphatic-Cy group,or Cy;

each Cy is independently an optionally substituted cyclic group selectedfrom a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, phenyl, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and a 5-6membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); and

each R is independently hydrogen, or an optionally substituted C₁₋₆aliphatic group, an optionally substituted phenyl, an optionallysubstituted 3-7 membered saturated or partially unsaturated carbocyclicring, an optionally substituted 3-7 membered saturated or partiallyunsaturated heterocyclic ring (having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur), or an optionallysubstituted 5-6 membered heteroaryl ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); or

two R groups on the same nitrogen are taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring (having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur);

wherein the compound is not Compound X, wherein Compound X is definedherein.

Overexpression of CDK2 is associated with abnormal regulation of thecell-cycle. The cyclin E/CDK2 complex plays an important role inregulation of the G1/S transition, histone biosynthesis and centrosomeduplication. Progressive phosphorylation of retinoblastoma (Rb) bycyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor,E2F, and promotes S-phase entry. Activation of cyclin A/CDK2 duringearly S-phase promotes phosphorylation of endogenous substrates thatpermit DNA replication and inactivation of E2F, for S-phase completion.(Asghar et al., Nat. Rev. Drug. Discov. 2015; 14(2): 130-146).

Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed incancer. Cyclin E amplification or overexpression has long beenassociated with poor outcomes in breast cancer. (Keyomarsi et al.,Cyclin E and survival in patients with breast cancer. N Engl J Med.(2002) 347:1566-75). Cyclin E2 (CCNE2) overexpression is associated withendocrine resistance in breast cancer cells and CDK2 inhibition has beenreported to restore sensitivity to tamoxifen or CDK4 inhibitors intamoxifen-resistant and CCNE2 overexpressing cells. (Caldon et al., Mol.Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Cancer Res. (2016)76: 2301-2313). Cyclin E amplification also reportedly contributes totrastuzumab resistance in HER2+ breast cancer. (Scaltriti et al., ProcNatl Acad Sci. (2011) 108: 3761-6). Cyclin E overexpression has alsobeen reported to play a role in basal-like and triple negative breastcancer (TNBC), as well as inflammatory breast cancer. (Elsawaf & Sinn,Breast Care (2011) 6:273-278; Alexander et al., Oncotarget (2017) 8:14897-14911.)

Amplification or overexpression of cyclin E1 (CCNE1) is also associatedwith poor outcomes in ovarian, gastric, endometrial and other cancers.(Nakayama et al., Gene amplification CCNE1 is related to poor survivaland potential therapeutic target in ovarian cancer, Cancer (2010) 116:2621-34; Etemadmoghadam et al., Clin Cancer Res (2013) 19: 5960-71;Au-Yeung et al., Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al.,Modern Pathology (2017) 30: 297-303; Ooi et al., Hum Pathol. (2017) 61:58-67; Noske et al., Oncotarget (2017) 8: 14794-14805).

There remains a need in the art for CDK inhibitors, especially selectiveCDK2 inhibitors, which may be useful for the treatment of cancer orother proliferative diseases or conditions. In particular, CDK2inhibitors may be useful in treating CCNE1 or CCNE2 amplified tumors.

2. Compounds and Definitions:

Compounds of this present disclosure include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this disclosure,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,101^(st) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 2005, and “March's Advanced Organic Chemistry:Reactions Mechanisms and Structure”, 8^(th) Ed., Ed.: Smith, M. B., JohnWiley & Sons, New York: 2019, the entire contents of which are herebyincorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1 to 6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1 to 5aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1to 4 aliphatic carbon atoms. In still other embodiments, aliphaticgroups contain 1 to 3 aliphatic carbon atoms, and in yet otherembodiments, aliphatic groups contain 1 to 2 aliphatic carbon atoms. Insome embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”)refers to a monocyclic C₃-C₆ hydrocarbon that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule. Suitable aliphatic groups include, but are not limited to,linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynylgroups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term “bicyclic ring” or “bicyclic ring system”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or having one or more units of unsaturation, having one ormore atoms in common between the two rings of the ring system. Thus, theterm includes any permissible ring fusion, such as ortho-fused orspirocyclic. As used herein, the term “heterobicyclic” is a subset of“bicyclic” that requires that one or more heteroatoms are present in oneor both rings of the bicycle. Such heteroatoms may be present at ringjunctions and are optionally substituted, and may be selected fromnitrogen (including N-oxides), oxygen, sulfur (including oxidized formssuch as sulfones and sulfonates), phosphorus (including oxidized formssuch as phosphonates and phosphates), boron, etc. In some embodiments, abicyclic group has 7-12 ring members and 0-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. As used herein, the term“bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclicor heterocyclic, saturated or partially unsaturated, having at least onebridge. As defined by IUPAC, a “bridge” is an unbranched chain of atomsor an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded tothree or more skeletal atoms (excluding hydrogen). In some embodiments,a bridged bicyclic group has 7-12 ring members and 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Such bridgedbicyclic groups are well known in the art and include those groups setforth below where each group is attached to the rest of the molecule atany substitutable carbon or nitrogen atom. Unless otherwise specified, abridged bicyclic group is optionally substituted with one or moresubstituents as set forth for aliphatic groups. Additionally oralternatively, any substitutable nitrogen of a bridged bicyclic group isoptionally substituted. Exemplary bicyclic rings include:

Exemplary bridged bicyclics include:

The term “Compound X” refers to5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)-N-(1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide.Compound X may also be depicted as

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen; or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom ina heterocyclic ring.

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of 4 to 14 ring members, wherein atleast one ring in the system is aromatic and wherein each ring in thesystem contains three to seven ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”. In certain embodiments of thepresent disclosure, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” in the context of “heteroaryl” particularly includes, butis not limited to, nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be monocyclic or bicyclic. A heteroaryl ring mayinclude one or more oxo (═O) or thioxo (═S) substituent. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring,” “heteroaryl group,” or “heteroaromatic,” any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7 to 10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably 1 to 4,heteroatoms, as defined above. When used in reference to a ring atom ofa heterocycle, the term “nitrogen” includes a substituted nitrogen. Asan example, in a saturated or partially unsaturated ring (having 0 to 3heteroatoms selected from oxygen, sulfur and nitrogen.

A heterocyclic ring can be attached to a provided compound at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be monocyclic orbicyclic, bridged bicyclic, or spirocyclic. A heterocyclic ring mayinclude one or more oxo (═O) or thioxo (═S) substituent. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the present disclosure may contain“substituted” moieties. In general, the term “substituted” means thatone or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at one or moresubstitutable position of the group, and when more than one position inany given structure is substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby the present disclosure are preferably those that result in theformation of stable or chemically feasible compounds. The term “stable,”as used herein, refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production, detection,and, in certain embodiments, their recovery, purification, and use forone or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₆R^(∘); —(CH₂)₀₋₆OR^(∘); —O(CH₂)₀₋₆R^(∘), —O—(CH₂)₀₋₆C(O)OR^(∘);—(CH₂)₀₋₆ CH(OR^(∘))₂; —(CH₂)₀₋₆ SR^(∘); —(CH₂)₀₋₆ Ph, which Ph may besubstituted with R^(∘); —(CH₂)₀₋₄₆O(CH₂)₀₋₁Ph which Ph may besubstituted with R^(∘); —CH═CHPh, which Ph may be substituted withR^(∘); —(CH₂)₀₋₆O(CH₂)₀₋₁-pyridyl which pyridyl may be substituted withR^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₆N(R^(∘))₂; —(CH₂)₀₋₆N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋ ₆N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₆N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₆C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₆C(O)OR^(∘);—(CH₂)₀₋₆C(O)SR^(∘); —(CH₂)₀₋₆C(O)OSiR^(∘) ₃; —(CH₂)₀₋₆OC(O)R^(∘);—OC(O)(CH₂)₀₋₆SR^(∘), —(CH₂)₀₋₆SC(O)R^(∘); —(CH₂)₀₋₆C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₆OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₆SSR^(∘); —(CH₂)₀₋₆S(O)₂R^(∘); —(CH₂)₀₋₆S(O)₂OR^(∘); —(CH₂)₀₋₆OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂; —(CH₂)₀₋₆S(O)R^(∘);—N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘);—C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —P(O)(OR^(∘))₂;—OP(O)(R^(∘))OR^(∘); —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄straight or branched) alkylene)O—N(R^(∘) ₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘) ₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH*₂— (5- to 6-membered heteroaryl ring), or a 3- to6-membered saturated, partially unsaturated, or aryl ring (having 0 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur),or, notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a 3- to12-membered saturated, partially unsaturated, or aryl mono- or bicyclicring (having 0 to 4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), —(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂R^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂ NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄ straight orbranched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5 to 6-membered saturated, partiallyunsaturated, or aryl ring (having 0 to 4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur). Suitable divalentsubstituents on a saturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR^(*)₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R^(*)₂))₂₋₃O—, or —S(C(R^(*) ₂))₂₋₃S—, wherein each independent occurrence ofR* is selected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, and an unsubstituted 5 to 6-membered saturated, partiallyunsaturated, or aryl ring (having 0 to 4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur). Suitable divalentsubstituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: —O(CR^(*) ₂)₂₋₃O—, wherein eachindependent occurrence of R* is selected from hydrogen, C₁₋₆ aliphaticwhich may be substituted as defined below, and an unsubstituted 5 to6-membered saturated, partially unsaturated, or aryl ring (having 0 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur).

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), —(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5 to 6-membered saturated, partially unsaturated, oraryl ring (having 0 to 4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur).

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†), —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5 to6-membered saturated, partially unsaturated, or aryl ring (having 0 to 4heteroatoms independently selected from nitrogen, oxygen, and sulfur),or, notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3 to 12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring (having 0 to 4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur).

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), —(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5 to 6- membered saturated, partially unsaturated, oraryl ring (having 0 to 4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur).

As used herein, the term “provided compound” or “compound of the presentdisclosure” refers to any genus, subgenus, and/or species set forthherein.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisdisclosure include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, andaryl sulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the disclosure. Unless otherwise stated, all tautomeric forms of thecompounds of the disclosure are within the scope of the disclosure.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present disclosure.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits CDK2 with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM, whenmeasured in an appropriate assay.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this disclosure include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisdisclosure that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this disclosureor an inhibitorily or degratorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof a CDK2 protein, or a mutant thereof

3. Description of Exemplary Embodiments:

In some embodiments, provided herein are compounds according to FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:

R^(A) is

L¹ is a covalent bond or a saturated or unsaturated, straight orbranched, optionally substituted bivalent C₁₋₆ hydrocarbon chain,wherein 0-2 methylene units of L¹ are independently replaced by —O—,—NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—,—S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—;

R¹ is hydrogen, an optionally substituted C₁₋₆ aliphatic group, or anoptionally substituted cyclic group selected from a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring, a 7-12membered saturated or partially unsaturated bicyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur);

R² is hydrogen, an optionally substituted C₁₋₆ aliphatic group, —C(O)OR,—C(O)NR₂, or an optionally substituted cyclic group selected from phenyland a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur);

each instance of R³ is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group;

R⁴ is a cyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 7-12 membered saturated orpartially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁵;

each instance of R⁵ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, an optionally substitutedC₁₋₆ aliphatic group, or an optionally substituted —C₁₋₆ aliphatic-Cygroup;

L² is a saturated or unsaturated, straight or branched, optionallysubstituted bivalent C₁₋₄ hydrocarbon chain, wherein 0-2 methylene unitsof L² are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—;

R⁶ is an optionally substituted C₁₋₆ aliphatic group, or a cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 7-12 membered saturated or partiallyunsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),and an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),wherein the cyclic group is optionally substituted with one or moreinstances of R⁷;

each instance of R⁷ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(O)S(O)₂R, —N(R)C(NR)NR₂, —N(R)S(O)₂N R₂, —N(R)S(O)₂R, anoptionally substituted C₁₋₆ aliphatic group, or Cy, or two instances ofR⁶ on the same carbon atom are taken together to form an oxo group;

L³ is a saturated or unsaturated, straight or branched, optionallysubstituted bivalent C₁₋₄ hydrocarbon chain, wherein 0-2 methylene unitsof L³ are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—;

R⁸ is a cyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 7-12 membered saturated orpartially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁹;

each instance of R⁹ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, an optionally substitutedC₁₋₆ aliphatic group, an optionally substituted C₁₋₆ aliphatic-Cy group,or Cy;

each Cy is independently an optionally substituted cyclic group selectedfrom a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, phenyl, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and a 5-6membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); and

each R is independently hydrogen, or an optionally substituted C₁₋₆aliphatic group, an optionally substituted phenyl, an optionallysubstituted 3-7 membered saturated or partially unsaturated carbocyclicring, an optionally substituted 3-7 membered saturated or partiallyunsaturated heterocyclic ring (having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur), or an optionallysubstituted 5-6 membered heteroaryl ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); or

two R groups on the same nitrogen are taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring (having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur);

wherein the compound is not Compound X, wherein Compound X is definedherein.

As defined generally above, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is selected from those depicted in thecompounds of the compounds of Table 1, below.

As defined generally above, L¹ is a covalent bond or a saturated orunsaturated, straight or branched, optionally substituted bivalent C₁₋₆hydrocarbon chain, wherein 0-2 methylene units of L¹ are independentlyreplaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—,—C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,or —NRC(O)NR—. In some embodiments, L¹ is a covalent bond. In someembodiments, L¹ is a saturated or unsaturated, straight or branched,optionally substituted bivalent C₁₋₆ hydrocarbon chain, wherein 0-2methylene units of L are independently replaced by —O—, —NR—, —S—,—OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—,—NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—. In someembodiments, L¹ is a saturated or unsaturated, straight or branched,optionally substituted bivalent C₁₋₆ hydrocarbon chain. In someembodiments, L¹ is a saturated or unsaturated, straight or branched,optionally substituted bivalent C₁₋₄ hydrocarbon chain. In someembodiments, L¹ is a saturated or unsaturated, straight or branched,optionally substituted bivalent C₁₋₆ hydrocarbon chain, wherein 1 or 2methylene units of L¹ are replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—. In some embodiments, L¹is an optionally substituted saturated, straight or branched, bivalentC₁₋₄ hydrocarbon chain. In some embodiments, L¹ is a partiallyunsaturated, straight or branched, bivalent C₁₋₄ hydrocarbon chain. Insome embodiments, L¹ is an optionally substituted saturated, straight,bivalent C₁₋₆ hydrocarbon chain, wherein 1-2 methylene units of L¹ areindependently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—,—S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—,—OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—. In some embodiments, L¹ is anoptionally substituted straight or branched C₁₋₆ alkylene chain, wherein1-2 methylene units of L¹ are independently replaced by —O—, —C(O)O—,—C(O)—, or —NRC(O)—. In some embodiments, L¹ is an optionallysubstituted straight or branched C₁₋₄ alkylene chain, wherein 1-2methylene units of L¹ are independently replaced by —O—, —C(O)O—,—C(O)—, or —NRC(O)—. In some embodiments, L¹ is an optionallysubstituted straight or branched C₁₋₄ alkylene chain, wherein 1methylene unit of L¹ is replaced by —O—. In some embodiments, L¹ is anoptionally substituted straight or branched C₁₋₄ alkylene chain, wherein1 methylene unit of L¹ is replaced by —NRC(O)—. In some embodiments, L¹is an optionally substituted straight or branched C₁₋₄ alkylene chain,wherein 1 methylene unit of L¹ is replaced by —NHC(O)— or —N(CH₃)C(O)—.In some embodiments, L¹ is an unsubstituted straight chain C₁₋₄alkylene. In some embodiments, L¹ is an unsubstituted straight chainC₁₋₄ alkenylene. In some embodiments, L¹ is an unsubstituted straightchain C₁₋₄ alkynylene. In some embodiments, L¹ is selected from thosedepicted in the compounds of Table 1, below.

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, L¹ is

As defined generally above, R¹ is hydrogen, an optionally substitutedC₁₋₆ aliphatic group, or an optionally substituted cyclic group selectedfrom a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, a 7-12 membered saturated or partially unsaturatedbicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromaticcarbocyclic ring, a 3-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring (having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur), a 7-12 membered saturatedor partially unsaturated bicyclic heterocyclic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur), a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur).

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is anoptionally substituted C₁₋₆ aliphatic group. In some embodiments, R¹ isan optionally substituted C₁₋₄ aliphatic group. In some embodiments, R¹is a C₁₋₄ aliphatic group. In some embodiments, R¹ is an isopropylgroup. In some embodiments, R¹ is a tert-butyl group. In someembodiments, R¹ is methyl.

In some embodiments, R¹ is an optionally substituted cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 7-12 membered saturated or partiallyunsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),and an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur).In some embodiments, R¹ is an optionally substituted cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur). In someembodiments, R¹ is an optionally substituted cyclic group selected fromphenyl, cyclohexyl, cyclopentyl, cycloheptyl, tetrahydrofuranyl,tetrahydropyranyl, pyridinyl, pyridazinyl, indole, and benzotriazole. Insome embodiments, R¹ is an optionally substituted phenyl group. In someembodiments, R¹ is an optionally substituted cyclohexyl group. In someembodiments, R¹ is an optionally substituted cyclopentyl group. In someembodiments, R¹ is an optionally substituted cycloheptyl group. In someembodiments, R¹ is an optionally substituted pyridinyl group. In someembodiments, R¹ is an optionally substituted pyridazinyl group. In someembodiments, R¹ is an optionally substituted tetrahydrofuranyl group. Insome embodiments, R¹ is an optionally substituted tetrahydropyranylgroup. In some embodiments, R¹ is an optionally substituted indolegroup. In some embodiments, R¹ is an optionally substitutedbenzotriazole group. In some embodiments, R¹ is selected from thosedepicted in the compounds of Table 1, below.

In some embodiments, R¹ is hydrogen, methyl,

In some embodiments, R¹ is

In some embodiments, R¹ is

As defined generally above, R² is hydrogen, an optionally substitutedC₁₋₆ aliphatic group, —C(O)OR, —C(O)NR₂, or an optionally substitutedcyclic group selected from phenyl and a 5-6 membered monocyclicheteroaromatic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur). In some embodiments, R² is an optionallysubstituted C₁₋₆ aliphatic group, —C(O)OR, —C(O)NR₂, or an optionallysubstituted cyclic group selected from phenyl and a 5-6 memberedmonocyclic heteroaromatic ring (having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur). In some embodiments, R² ishydrogen, methyl, —C(O)NHCH₃, —C(O)NH₂, —C(O)OCH₃, —C(O)OH, or anoptionally substituted 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur). In some embodiments, R² is hydrogen, methyl, —C(O)NHCH₃,—C(O)NH₂, —C(O)OCH₃, or —C(O)OH. In some embodiments, R² is hydrogen. Insome embodiments, R² is methyl. In some embodiments, R² is —C(O)NHCH₃.In some embodiments, R² is —C(O)NH₂. In some embodiments, R² is—C(O)OCH₃. In some embodiments, R² is —C(O)OH. In some embodiments, R²is a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur). In someembodiments R² is an oxazolyl group. In some embodiments, R² is apyrimidinyl group.

In some embodiments, R² is selected from those depicted in the compoundsof Table 1, below.

As defined generally above, each instance of R³ is independentlyhydrogen or an optionally substituted C₁₋₆ aliphatic group. In someembodiments, each instance of R³ is hydrogen.

As defined generally above, R⁴ is a cyclic group selected from a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,a 7-12 membered saturated or partially unsaturated bicyclic carbocyclicring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur), wherein the cyclic group is optionally substituted with oneor more instances of R⁵.

In some embodiments, R⁴ is a cyclic group selected from a 3-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring (having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur), and a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),wherein the cyclic group is optionally substituted with one or moreinstances of R⁵. In some embodiments, R⁴ is a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur),optionally substituted with one or more instances of R⁵. In someembodiments, R⁴ is a 5-6 membered monocyclic heteroaromatic ring (having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur), optionally substituted with one or more instances of R⁵. Insome embodiments, R⁴ is a cyclic group selected from phenyl, pyridine,and piperidine, wherein the cyclic group is optionally substituted withone or more instances of R⁵. In some embodiments, R⁴ is phenyl,optionally substituted with one or more instances of R⁵. In someembodiments, R⁴ is pyridine, optionally substituted with one or moreinstances of R⁵. In some embodiments, R⁴ is piperidine, optionallysubstituted with one or more instances of R⁵. In some embodiments, R⁴ isselected from those depicted in the compounds of Table 1, below.

In some embodiments, R⁴ is substituted with 0, 1, or 2 instances of R⁵.In some embodiments, R⁴ is substituted with 1 instance of R⁵. R³ issubstituted with 2 instances of R⁵. R⁴ is substituted with 3 instancesof R⁵. In some embodiments, R⁴ is unsubstituted.

As defined generally above, each instance of R⁵ is independentlyhalogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂,—N(R)S(O)₂R, an optionally substituted C₁₋₆ aliphatic group, or anoptionally substituted —C₁₋₆ aliphatic-Cy group.

In some embodiments, R⁵ is —OR, —C(O)R, an optionally substituted C₁₋₆aliphatic group, or an optionally substituted —C₁₋₆ aliphatic-Cy group.In some embodiments, R⁵ is —OR. In some embodiments, R⁵ is —C(O)R. Insome embodiments, R⁵ is an optionally substituted C₁₋₆ aliphatic group.In some embodiments, R⁵ is an optionally substituted —C₁₋₆ aliphatic-Cygroup. In some embodiments, R⁵ is an optionally substituted benzylgroup, an optionally substituted benzoyl group, an optionallysubstituted phenoxy group, or an optionally substituted phenylacetylgroup. In some embodiments R⁵ is an optionally substituted benzyl group.In some embodiments R⁵ is an optionally substituted benzoyl group. Insome embodiments R⁵ is an optionally substituted phenoxy group. In someembodiments R⁵ is an optionally substituted phenylacetyl group. In someembodiments, R⁵ is selected from those depicted in the compounds ofTable 1, below.

In some embodiments, R⁴ is

In some embodiments, R^(A) is a substituent of Table A1 or Table A2:

TABLE A1 Exemplary R^(A) substituents

TABLE A2 Additional Exemplary R^(A) substituents

In some embodiments, R^(A) is a substituent of Table A1 or Table A2. Insome embodiments, R^(A) is a substituent of Table A1. In someembodiments, R^(A) is a substituent of Table A2.

In some embodiments, R^(A) is

As defined generally above, L² is a saturated or unsaturated, straightor branched, optionally substituted bivalent C₁₋₄ hydrocarbon chain,wherein 0-2 methylene units of L² are independently replaced by —O—,—NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—,—S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—. Insome embodiments, L² is a saturated, straight, optionally substitutedbivalent C₁₋₄ hydrocarbon chain, wherein 0-2 methylene units of L² areindependently replaced by —O—, —NR—, —OC(O)—, —C(O)O—, —C(O)—, —NRC(O)—,or —C(O)NR. In some embodiments, L² is a saturated, straight, optionallysubstituted bivalent C₁₋₄ hydrocarbon chain. In some embodiments, L² isa saturated, straight, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 1 methylene unit of L² is replaced by —O—, —NR—, —OC(O)—,—C(O)O—, —C(O)—, —NRC(O)—, or —C(O)NR. In some embodiments, L² is asaturated, straight, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 1 methylene unit of L² is replaced by —C(O)—. In someembodiments, L² is —CH₂— or —C(O)—. In some embodiments, L² is —CH₂—. Insome embodiments, L² is —C(O)—. In some embodiments, L² is selected fromthose depicted in the compounds of Table 1, below.

As generally defined above, R⁶ is an optionally substituted C₁₋₆aliphatic group, or a cyclic group selected from a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring, a 7-12membered saturated or partially unsaturated bicyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur), wherein the cyclic group is optionally substituted with oneor more instances of R⁷.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphaticgroup. In some embodiments, R⁶ is a cyclic group selected from a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,a 7-12 membered saturated or partially unsaturated bicyclic carbocyclicring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur), wherein the cyclic group is optionally substituted with oneor more instances of R⁷. In some embodiments, R⁶ is a cyclic groupselected from phenyl, an 8-10 membered bicyclic aromatic carbocyclicring, a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),and an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),wherein the cyclic group is optionally substituted with one or moreinstances of R⁷.

In some embodiments, R⁶ is a cyclic group selected from cyclohexyl,phenyl, quinolinyl, isoquinolinyl, quinoxalinyl,2,3-dihydrobenzo[b][1,4]dioxinyl, pyrazolyl, isoxazolyl, imidazolyl,thiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,2,3-dihydrobenzo[d]furanyl, benzofuranyl, indolyl, benzo[1,2,3]triazole,benzimidazolyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl,indazolyl, indolinyl, indolizinyl, isoindolinyl, and2,3,-dihydrobenzo[d]oxazolyl, wherein the cyclic group is optionallysubstituted with one or more instances of R⁷.

In some embodiments, R⁶ is cyclohexyl, optionally substituted with oneor more instances of R⁷. In some embodiments, R⁶ is phenyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ isquinolinyl, optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is isoquinolinyl, optionally substituted with oneor more instances of R⁷. In some embodiments, R⁶ is quinoxalinyl,optionally substituted with one or more instances of R⁷. In someembodiments, R⁶ is 2,3-dihydrobenzo[b][1,4]dioxinyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ ispyrazolyl, optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is isoxazolyl, optionally substituted with one ormore instances of R⁷. In some embodiments, R⁶ is imidazolyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ isthiazolyl, optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is pyridinyl, optionally substituted with one ormore instances of R⁷. In some embodiments, R⁶ is pyrazinyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ ispyridazinyl, optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is pyrimidinyl, optionally substituted with one ormore instances of R⁷. In some embodiments, R⁶ is2,3-dihydrobenzo[d]furanyl, optionally substituted with one or moreinstances of R⁷. In some embodiments, R⁶ is benzofuranyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁵ isindolyl, optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is benzo[1,2,3]triazole, optionally substitutedwith one or more instances of R⁷. In some embodiments, R⁶ isbenzimidazolyl, optionally substituted with one or more instances of R⁷.In some embodiments, R⁶ is imidazo[1,2-a]pyrimidinyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ isimidazo[1,2-a]pyrazinyl, optionally substituted with one or moreinstances of R⁷. In some embodiments, R⁶ is indazolyl, optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ isindolinyl, optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is indolizinyl, optionally substituted with one ormore instances of R⁷. In some embodiments, R⁶ is isoindolinyl,optionally substituted with one or more instances of R⁷. In someembodiments, R⁶ is 2,3,-dihydrobenzo[d]oxazolyl, optionally substitutedwith one or more instances of R⁷. In some embodiments, R⁶ is selectedfrom those depicted in the compounds of Table 1, below.

In some embodiments, R⁶ is substituted with 0, 1, 2 or 3 instances ofR⁷. In some embodiments, R⁶ is substituted with 1 instance of R⁷. R⁶ issubstituted with 2 instances of R⁷. R⁶ is substituted with 3 instancesof R⁷. In some embodiments, R⁶ is unsubstituted.

As defined generally above, each R⁷ is independently halogen, —CN, —NO₂,—OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(O)S(O)₂R, —N(R)C(NR)NR₂, —N(R)S(O)₂N R₂,—N(R)S(O)₂R, an optionally substituted C₁₋₆ aliphatic group, or Cy, ortwo instances of R⁶ on the same carbon atom are taken together to forman oxo group.

In some embodiments, each R⁷ is independently halogen, —CN, —OR, —NR₂,—S(O)₂NR₂, —N(R)C(O)R, —N(R)C(O)S(O)₂R, an optionally substituted C₁₋₆aliphatic group, or Cy, or two instances of R⁷ on the same carbon atomare taken together to form an oxo group. In some embodiments, each R⁷ isindependently —OR, an optionally substituted C₁₋₆ aliphatic group, Cy ortwo instances of R⁷ on the same carbon atom are taken together to forman oxo group.

In some embodiments, each R⁷ is independently fluoro, chloro, methoxy,ethoxy, isopropoxy, cyclopropoxy, isobutoxy, phenoxy,2-cyclopropylethoxy, methyl, ethyl, cyclopropyl, isobutyl, phenyl,pyridinyl, pyrimidinyl, cyclopropanecarboxamido, 2-cyclopropylacetamido,(methyl sulfonyl)methanamido, cyano, hydroxymethyl, trifluoromethoxy,trifluoromethyl, sulfamoyl, or amino, or two instances of R⁷ on the samecarbon atom are taken together to form an oxo group. In someembodiments, each R⁷ is independently —OR. In some embodiments, each R⁷is independently selected from those depicted in the compounds of Table1, below.

In some embodiments, —L²—R⁶ is a substituent of Table B1 or Table B2:

TABLE B1 Exemplary -L²—R⁶ substituents

TABLE B2 Additional Exemplary -L²—R⁶ substituents

In some embodiments, —L²—R⁶ is a substituent of Table B1. In someembodiments, —L²—R⁶ is a substituent of Table B2. In some embodiments,—L²—R⁶ is

As defined generally above, L³ is a saturated or unsaturated, straightor branched, optionally substituted bivalent C₁₋₄ hydrocarbon chain,wherein 0-2 methylene units of L³ are independently replaced by —O—,—NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—,—S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—. Insome embodiments, L³ is a saturated, straight, optionally substitutedbivalent C₁₋₄ hydrocarbon chain, wherein 0-2 methylene units of L³ areindependently replaced by —O—, —NR—, —OC(O)—, —C(O)O—, —C(O)—, —NRC(O)—,or —C(O)NR. In some embodiments, L³ is a saturated, straight, optionallysubstituted bivalent C₁₋₄ hydrocarbon chain. In some embodiments, L³ isa saturated, straight, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 1 methylene unit of L³ is replaced by —O—, —NR—, —OC(O)—,—C(O)O—, —C(O)—, —NRC(O)—, or —C(O)NR. In some embodiments, L³ is asaturated, straight, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 1 methylene unit of L³ is replaced by —C(O)—. In someembodiments, L³ is a saturated, straight, substituted bivalent C₁₋₄hydrocarbon chain, wherein 1 methylene unit of L³ is replaced by —C(O)—,and wherein the C₁₋₄ hydrocarbon chain is substituted twice on the samecarbon atom and forms a 3-6 membered saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments, L³ is —C(O)CH₂—,—C(O)C(CH₃)H—, —C(O)C(CH₃)₂—, —C(O)CH₂CH₂—, C(O)CH₂CH₂CH₂—,

or —C(O)—. In some embodiments, L³ is —C(O)CH₂—, or —C(O)C(CH₃)H—. Insome embodiments, L³ is —C(O)CH₂—. In some embodiments, L³ is—C(O)C(CH₃)H—. In some embodiments, L³ is —C(O)C(CH₃)₂—. In someembodiments, L³ is —C(O)CH₂CH₂—. In some embodiments, L³ is—C(O)CH₂CH₂CH₂—. In some embodiments, L³ is —C(O)—. In some embodiments,L³ is

In some embodiments, L³ is —C(O)CH₂—,

or —C(O)C(CH₃)H—. In some embodiments, L³ is selected from thosedepicted in the compounds of Table 1, below.

As defined generally above, R⁸ is a cyclic group selected from a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,a 7-12 membered saturated or partially unsaturated bicyclic carbocyclicring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur), wherein the cyclic group is optionally substituted with oneor more instances of R⁹.

In some embodiments, R⁸ is a cyclic group selected from phenyl, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur), wherein the cyclic group is optionally substituted with oneor more instances of R⁹. In some embodiments, R⁸ is an 8-10 memberedbicyclic heteroaromatic ring (having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur), optionally substituted withone or more instances of R⁹. In some embodiments, R⁸ a cyclic groupselected from indolyl, indazolyl, benzimidazolyl, benzofuranyl, phenyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl,isoquinolinyl, pyrazolyl, tetrazolyl, quinoxalinyl, indolizinyl,thiazolyl, oxazolyl, pyrrolyl, imidazo[1,2-a]pyrazinyl, andtetrahydropyranyl wherein the cyclic group is optionally substitutedwith one or more instances of R⁹. In some embodiments, R⁸ is a cyclicgroup selected from indolyl, indazolyl, benzofuranyl, andbenzimidazolyl, wherein the cyclic group is optionally substituted withone or more instances of R⁹.

In some embodiments, R⁸ is indolyl optionally substituted with one ormore instances of R⁹. In some embodiments, R⁸ is indazolyl, optionallysubstituted with one or more instances of R⁹. In some embodiments, R⁸ isbenzimidazolyl, optionally substituted with one or more instances of R⁹.In some embodiments, R⁸ is benzofuranyl, optionally substituted with oneor more instances of R⁹. In some embodiments, R⁸ is phenyl, optionallysubstituted with one or more instances of R⁹. In some embodiments, R⁸ ispyridinyl, optionally substituted with one or more instances of R⁹. Insome embodiments, R⁸ is pyrimidinyl, optionally substituted with one ormore instances of R⁹. In some embodiments, R⁸ is pyridazinyl, optionallysubstituted with one or more instances of R⁹. In some embodiments, R⁸ ispyrazinyl, optionally substituted with one or more instances of R⁹. Insome embodiments, R⁸ is quinolinyl, optionally substituted with one ormore instances of R⁹. In some embodiments, R⁸ is isoquinolinyl,optionally substituted with one or more instances of R⁹. In someembodiments, R⁸ is pyrazolyl, optionally substituted with one or moreinstances of R⁹. In some embodiments, R⁸ is tetrazolyl, optionallysubstituted with one or more instances of R⁹. In some embodiments, R⁸ isquinoxalinyl, optionally substituted with one or more instances of R⁹.In some embodiments, R⁸ is indolizinyl, optionally substituted with oneor more instances of R⁹. In some embodiments, R⁸ is thiazolyl,optionally substituted with one or more instances of R⁹. In someembodiments, R⁸ is oxazolyl, optionally substituted with one or moreinstances of R⁹. In some embodiments, R⁸ is pyrrolyl, optionallysubstituted with one or more instances of R⁹. In some embodiments, R⁸ isimidazo[1,2-a]pyrazinyl, optionally substituted with one or moreinstances of R⁹. In some embodiments, R⁸ is tetrahydropyranyl,optionally substituted with one or more instances of R⁹. In someembodiments, R⁸ is selected from those depicted in the compounds ofTable 1, below.

In some embodiments, R⁸ is substituted with 0, 1 or 2 instances of R⁹.In some embodiments, R⁸ is substituted with 1 instance of R⁹. R⁸ issubstituted with 2 instances of R⁹. In some embodiments, R⁸ isunsubstituted.

As defined generally above, each instance of R⁹ is independentlyhalogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂,—N(R)S(O)₂R, an optionally substituted C₁₋₆ aliphatic group, anoptionally substituted C₁₋₆ aliphatic-Cy group, or Cy.

In some embodiments, each instance of R⁹ is independently halogen, —CN,—OR, an optionally substituted C₁₋₆ aliphatic group, or Cy. In someembodiments, each instance of R⁹ is independently halogen, —CN, —OR, ora C₁₋₆ aliphatic group. In some embodiments, each instance of R⁹ isindependently fluoro, chloro, bromo, —CN, methyl, ethyl methoxy,hydroxymethyl, cyclopropylmethoxy, 2-methoxyethyl, phenyl or pyridinyl.In some embodiments, each instance of R⁹ is independently chloro, bromo,—CN, methyl, or methoxy. In some embodiments, each R⁹ is independentlyselected from those depicted in the compounds of Table 1, below.

In some embodiments, —L³—R⁸ is a substituent of Table C1 or Table C2:

TABLE C1 Exemplary -L³—R⁸ substituents

TABLE C2 Additional Exemplary -L³—R⁸ substituents

In some embodiments, —L³—R⁸ is a substituent of Table C1. In someembodiments, —L³—R⁸ is a substituent of Table C2. In some embodiments,—L³—R⁸ is

In some embodiments, each instance of Cy is independently phenyl or a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur).

In some embodiments:

R^(A) is

R¹ is a C₁₋₄ aliphatic group or an optionally substituted cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur);

R² is hydrogen, methyl, —C(O)NHCH₃, —C(O)NH₂, —C(O)OCH₃, —C(O)OH, or anoptionally substituted 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur);

R⁴ is a cyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and a 5-6membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), wherein thecyclic group is optionally substituted with one or more instances of R⁵;

each R⁵ is independently —OR, —C(O)R, an optionally substituted C₁₋₆aliphatic group, or an optionally substituted —C₁₋₆ aliphatic-Cy group;

L² is —C(O)—;

R⁶ is a cyclic group selected from phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁷;

each R⁷ is independently —OR, an optionally substituted C₁₋₆ aliphaticgroup, Cy or two instances of R⁷ on the same carbon atom are takentogether to form an oxo group;

L³ is —C(O)CH₂—,

or —C(O)C(CH₃)H—;

R⁸ is an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),optionally substituted with one or more instances of R⁹;

each instance of R⁹ is independently halogen, —CN, —OR, or a C₁₋₆aliphatic group; and

each instance of Cy is independently phenyl or a 5-6 membered monocyclicheteroaromatic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur).

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶, L³and R⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, —L²—R⁶ is a substituent from Table B1. In someembodiments, —L³—R⁸ is a substituent from Table C1. In some embodiments,R^(A) is a substituent from Table A1, and —L²—R⁶ is a substituent fromTable B1. In some embodiments, R^(A) is a substituent from Table A1, and—L³—R⁸ is a substituent from Table C1. In some embodiments, —L²—R⁶ is asubstituent from Table B1, and —L³—R⁸ is a substituent from Table C1.And in some embodiments, R^(A) is a substituent from Table A1, —L²—R⁶ isa substituent from Table B1, and —L³—R⁸ is a substituent from Table C1.In some embodiments:

R^(A) is

L¹ is

R¹ is a C₁₋₄ aliphatic group or an optionally substituted cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur);

R² is hydrogen, methyl, —C(O)NHCH₃, —C(O)NH₂, —C(O)OCH₃, —C(O)OH, or a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur);

R⁴ is a 3-8 membered saturated or partially unsaturated monocyclicheterocyclic ring (having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), optionally substituted with one or moreinstances of R⁵;

each R⁵ is independently —OR, —C(O)R, an optionally substituted C₁₋₆aliphatic group, or an optionally substituted —C₁₋₆ aliphatic-Cy group;

L² is —C(O)—;

R⁶ is a cyclic group selected from phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁷;

each R⁷ is independently —OR, an optionally substituted C₁₋₆ aliphaticgroup, Cy or two instances of R⁷ on the same carbon atom are takentogether to form an oxo group;

L³ is —C(O)CH₂—,

or —C(O)C(CH₃)H—;

R⁸ is an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),optionally substituted with one or more instances of R⁹;

each instance of R⁹ is independently halogen, —CN, —OR, or a C₁₋₆aliphatic group; and

each instance of Cy is independently phenyl or a 5-6 membered monocyclicheteroaromatic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur).

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², L¹, L²,R⁶, L³ and R⁸, and their constituent groups, are each as defined anddescribed herein. In some embodiments, —L²—R⁶ is a substituent fromTable B1. In some embodiments, —L³—R⁸ is a substituent from Table C1. Insome embodiments, —L²—R⁶ is a substituent from Table B1, and —L³—R⁸ is asubstituent from Table C1. In some embodiments, R¹ is optionallysubstituted phenyl. In some embodiments, R¹ is optionally substitutedcyclohexyl. In some embodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, R² is —C(O)NHCH₃. In some embodiments, L² is—C(O)—. In some embodiments, R⁶ is phenyl optionally substituted withone or more instances of R⁷. In some embodiments, R⁶ is pyrazolyloptionally substituted with one or more instances of R⁷. In someembodiments, L³ is —C(O)CH₂—. In some embodiments, L³ is —C(O)C(CH₃)H—.In some embodiments, R⁸ is a cyclic group selected from indolyl,indazolyl, benzofuranyl, and benzimidazolyl, wherein the cyclic group isoptionally substituted with one or more instances of R⁹. In someembodiments, R⁸ is indolyl optionally substituted with one or moreinstances of R⁹.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein R⁴, L², R⁶, L³and R⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, —L²—R⁶ is a substituent from Table B1. Insome embodiments, —L³—R⁸ is a substituent from Table C1. In someembodiments, —L²—R⁶ is a substituent from Table B1, and —L³—R⁸ is asubstituent from Table C1. In some embodiments, R⁴ is pyridinyl,optionally substituted with one or more instances of R⁵. In someembodiments, R⁴ is piperidinyl, optionally substituted with one or moreinstances of R⁵. In some embodiments, L² is —C(O)—. In some embodiments,R⁶ is phenyl optionally substituted with one or more instances of R⁷. Insome embodiments, R⁶ is pyrazolyl optionally substituted with one ormore instances of R⁷. In some embodiments, L³ is —C(O)CH₂—. In someembodiments, L³ is —C(O)C(CH₃)H—. In some embodiments, R⁸ is a cyclicgroup selected from indolyl, indazolyl, benzofuranyl, andbenzimidazolyl, wherein the cyclic group is optionally substituted withone or more instances of R⁹. In some embodiments, R⁸ is indolyloptionally substituted with one or more instances of R⁹.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein R^(A), R⁶, L³ andR⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, —L³—R⁸ is a substituent from Table C1. In someembodiments, R^(A) is a substituent from Table A1, and —L³—R⁸ is asubstituent from Table C1. In some embodiments, R⁶ is phenyl optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁶ ispyrazolyl optionally substituted with one or more instances of R⁷.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula Va or Vb:

or a pharmaceutically acceptable salt thereof, wherein R^(A), R⁷, L³ andR⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, —L³—R⁸ is a substituent from Table C1. In someembodiments, R^(A) is a substituent from Table A1, and —L³—R⁸ is asubstituent from Table C1. In some embodiments, each instance of R⁷ is—OR or a halogen. In some embodiments, each instance of R⁷ is —OR. Insome embodiments, L³ is —C(O)CH₂—. In some embodiments, L³ is—C(O)C(CH₃)H—. In some embodiments, R⁸ is a cyclic group selected fromindolyl, indazolyl, benzofuranyl, and benzimidazolyl, wherein the cyclicgroup is optionally substituted with one or more instances of R⁹. Insome embodiments, R⁸ is indolyl optionally substituted with one or moreinstances of R⁹.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶,and R⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, —L²—R⁶ is a substituent from Table B1. In someembodiments, R^(A) is a substituent from Table A1, and —L²—R⁶ is asubstituent from Table B1. In some embodiments, R⁸ is a cyclic groupselected from indolyl, indazolyl, benzofuranyl, and benzimidazolyl,wherein the cyclic group is optionally substituted with one or moreinstances of R⁹. In some embodiments, R⁸ is indolyl optionallysubstituted with one or more instances of R⁹.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIa:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶,and R⁹, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, —L²—R⁶ is a substituent from Table B1. In someembodiments, R^(A) is a substituent from Table A1, and —L²—R⁶ is asubstituent from Table B1. In some embodiments, R⁹ is a halogen, methylor —CN. In some embodiments, R⁹ is chloro.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIIa:

or a pharmaceutically acceptable salt thereof, wherein R^(A), R⁶, andR⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, R⁶ is phenyl optionally substituted with one or moreinstances of R⁷. In some embodiments, R⁶ is pyrazolyl optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁸ isa cyclic group selected from indolyl, indazolyl, benzofuranyl, andbenzimidazolyl, wherein the cyclic group is optionally substituted withone or more instances of R⁹. In some embodiments, R⁸ is indolyloptionally substituted with one or more instances of R⁹.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIIb:

or a pharmaceutically acceptable salt thereof, wherein R^(A), R⁶, andR⁹, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, R⁶ is phenyl optionally substituted with one or moreinstances of R⁷. In some embodiments, R⁶ is pyrazolyl optionallysubstituted with one or more instances of R⁷. In some embodiments, R⁹ isa halogen, methyl or —CN. In some embodiments, R⁹ is chloro.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIIc:

or a pharmaceutically acceptable salt thereof, wherein R^(A), R⁷, andR⁸, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, each instance of R⁷ is —OR or a halogen. In someembodiments, each instance of R⁷ is —OR. In some embodiments, L³ is—C(O)CH₂—. In some embodiments, L³ is —C(O)C(CH₃)H—. In someembodiments, R⁸ is a cyclic group selected from indolyl, indazolyl,benzofuranyl, and benzimidazolyl, wherein the cyclic group is optionallysubstituted with one or more instances of R⁹. In some embodiments, R⁸ isindolyl optionally substituted with one or more instances of R⁹.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIIe or VIIf:

or a pharmaceutically acceptable salt thereof, wherein R^(A), R⁷, andR⁹, and their constituent groups, are each as defined and describedherein. In some embodiments, R^(A) is a substituent from Table A1. Insome embodiments, each instance of R⁷ is —OR or a halogen. In someembodiments, each instance of R⁷ is —OR. In some embodiments, R⁹ is ahalogen, methyl or —CN. In some embodiments, R⁹ is chloro.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIIIa or VIIIb

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁷, andR⁹, and their constituent groups, are each as defined and describedherein. In some embodiments, R¹ is optionally substituted phenyl. Insome embodiments, R¹ is optionally substituted cyclohexyl. In someembodiments, L¹ is

In some embodiments, L¹ is

In some embodiments, R² is —C(O)NHCH₃. In some embodiments, eachinstance of R⁷ is —OR or a halogen. In some embodiments, each instanceof R⁷ is —OR. In some embodiments, R⁹ is a halogen, methyl or —CN. Insome embodiments, R⁹ is chloro.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula VIIIc or VIIId:

or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁷, and R⁹,and their constituent groups, are each as defined and described herein.In some embodiments, R⁴ is pyridinyl, optionally substituted with one ormore instances of R⁵. In some embodiments, R⁴ is piperidinyl, optionallysubstituted with one or more instances of R⁵. In some embodiments, eachinstance of R⁷ is —OR or a halogen. In some embodiments, each instanceof R⁷ is —OR. In some embodiments, R⁹ is a halogen, methyl or —CN. Insome embodiments, R⁹ is chloro.

Exemplary compounds of the present disclosure are set forth in Table 1,below.

TABLE 1 Exemplary Compounds # Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

First eluting diastereomer I-23

Second eluting diastereomer I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

First eluting diastereomer I-87

Second eluting diastereomer I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

First eluting diastereomer I-101

Second eluting diastereomer I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

First eluting diastereomer I-111

Second eluting diastereomer I-112

I-113

I-114

I-115

I-116

I-117

First eluting diastereomer I-118

Second eluting diastereomer I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

First eluting diastereomer - n-Hexane/EtOH I-146

Second eluting diastereomer - n-Hexane/EtOH I-147

First eluting diastereomer - H₂O/Acetonitrile I-148

Second eluting diastereomer - H₂O/Acetonitrile I-149

I-150

I-151

I-152

First eluting diastereomer I-153

Second eluting diastereomer I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

First eluting diastereomer I-195

Second eluting diastereomer I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

First eluting diastereomer I-233

Second eluting diastereomer I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

Synthesized from first eluting intermediate I-258

Synthesized from second eluting intermediate I-259

First eluting diastereomer I-260

Second eluting diastereomer I-261

First eluting enantiomer I-262

Second eluting enantiomer

In some embodiments, the present disclosure provides a compound setforth in Table 1, above, or a pharmaceutically acceptable salt thereof.In some embodiments, the disclosure provides a compound set forth inTable 1, above, or a pharmaceutically acceptable salt thereof, and anyenantiomers, diastereomers, or conformation isomers thereof.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, excipient, vehicle, adjuvant ordiluent. In some embodiments, the present disclosure provides apharmaceutical composition comprising a compound set forth in Table 1above, or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, excipient, vehicle, adjuvant ordiluent. In some embodiments, the pharmaceutical composition furthercomprises an additional therapeutic agent.

In some embodiments, the present disclosure provides a complexcomprising a CDK2 protein and a compound of the present disclosure.

In some embodiments, the present disclosure provides a method ofinhibiting the activity of a cyclin-dependent kinase (CDK). In someembodiments, the method comprises contacting a compound of the presentdisclosure with a CDK. In some embodiments, the compound and the CDK arecontacted in vivo. In some embodiments, the compound and the CDK arecontacted in vitro.

In some embodiments, the present disclosure provides compounds thatselectively inhibit CDK2 over other cyclin-dependent kinases (CDKs). Insome embodiments, the compounds of the present disclosure selectivelyinhibit CDK2 over one or more other CDKs, selected from CDK1, CDK3,CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12 and CDK13. Insome embodiments, the compounds of the present disclosure selectivelyinhibit CDK2 over CDK4. In some embodiments, the compounds of thepresent disclosure selectively inhibit CDK2 over CDK6. In someembodiments, the compounds of the present disclosure selectively inhibitCDK2 over CDK4 and CDK6.

In some embodiments, the present disclosure provides compounds thatselectively inhibit CDK2/cyclin E complexes over other CDK complexes.

In any of the preceding embodiments, the central bicyclic core of any ofthe compounds or formulas described herein can be in one of a number ofstereochemical configurations, or a mixture of two or morestereochemical configurations.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶, L³and R⁸, and their constituent groups, are each as defined and describedherein.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶, L³and R⁸, and their constituent groups, are each as defined and describedherein.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶, L³and R⁸, and their constituent groups, are each as defined and describedherein.

In some embodiments, the present disclosure provides a compound ofFormula I, which is a compound of Formula Id:

or a pharmaceutically acceptable salt thereof, wherein R^(A), L², R⁶, L³and R⁸, and their constituent groups, are each as defined and describedherein.

In some embodiments, the present disclosure provides a compound of anyone of Formulas II, III, IV, V, Va, Vb, VI, VIa, VIIa, VIIb, VIIc, VIId,VIIe, VIIf, VIIIa, VIIIb, VIIIc, or VIIId, or a compound of Table 1, ora pharmaceutically acceptable salt thereof, wherein the central bicycliccore of said Formula or compound has a stereochemical configuration asshown below:

or a combination of two or more of the aforementioned stereochemicalconfigurations. In some embodiments, the compound has stereochemicalconfiguration “(a)”. In some embodiments, the compound hasstereochemical configuration “(b)”. In some embodiments, the compoundhas stereochemical configuration “(c)”. In some embodiments, thecompound has stereochemical configuration “(d)”. In some embodiments,the compound has stereochemical configuration “(e)”. In someembodiments, the compound has stereochemical configuration “(f)”. Insome embodiments, the compound has stereochemical configuration “(g)”.In some embodiments, the compound has stereochemical configuration“(h)”.

4. General Methods of Providing the Present Compounds

The compounds of this disclosure may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group (“PG”),leaving group (“LG”), or transformation condition is depicted, one ofordinary skill in the art will appreciate that other protecting groups,leaving groups, and transformation conditions are also suitable and arecontemplated. Such groups and transformations are described in detail inMarch's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, M. B. Smith and J. March, 5^(th) Edition, John Wiley & Sons,2001, Comprehensive Organic Transformations, R. C. Larock, 2^(nd)Edition, John Wiley & Sons, 1999, and Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, the entirety of each of which is hereby incorporated hereinby reference.

As used herein, the phrase “leaving group” (LG) includes, but is notlimited to, halogens (e.g. fluoride, chloride, bromide, iodide),sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate,nosylate, triflate), diazonium, and the like.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Suitable aminoprotecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

Compounds of the present disclosure, including those of Formula I andthe compounds of Table 1, can generally be prepared according themethods described below. Reagents and conditions can be modified andsubstituted using knowledge common to one of ordinary skill in the art,as needed, in order to arrive at the compounds of the presentdisclosure.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the disclosure provides a compositioncomprising a compound of this disclosure or a pharmaceuticallyacceptable derivative thereof and a pharmaceutically acceptable carrier,adjuvant, or vehicle. The amount of compound in compositions of thisdisclosure is such that it is effective to measurably inhibit a CDK2protein, or a mutant thereof, in a biological sample or in a patient. Incertain embodiments, the amount of compound in compositions of thisdisclosure is such that it is effective to measurably inhibit a CDK2protein, or a mutant thereof, in a biological sample or in a patient. Incertain embodiments, a composition of this disclosure is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this disclosure is formulated for oraladministration to a patient.

Compositions of the present disclosure may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this disclosure may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this disclosure may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisdisclosure may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this disclosure may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this disclosureinclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this disclosure may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisdisclosure are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this disclosure areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered with food.

The amount of compounds of the present disclosure that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present disclosure in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for themodulation of the activity CDK2. In some embodiments, the compounds andcompositions described herein are CDK2 inhibitors.

In some embodiments, the compounds and compositions of the presentdisclosure are useful for treating diseases and disorders associatedwith CDK2 activity, including, but not limited to cancers,myeloproliferative disorders, autoimmune disorders, inflammatorydisorders, viral infections, fibrotic disorders, and neurodegenerativedisorders.

In some embodiments, the disclosure provides a method of inhibiting theactivity of a CDK2, the method comprising contacting a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof withthe CDK2. In some embodiments, the contacting takes place in vitro. Insome embodiments, the contacting takes place in vivo.

In some embodiments, the disclosure provides a method of treating,preventing or lessening the severity of a disease or disorder associatedwith CDK2 activity in a patient, including, but not limited to cancers,myeloproliferative disorders, autoimmune disorders, inflammatorydisorders, fibrotic disorders, and neurodegenerative disorders, saidmethod comprising administering to a patient in need thereof, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising an effective amountof a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof.

The disclosure further provides a compound of the present disclosure, ora pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising an effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, for use inthe treatment of a disease or disorder associated with CDK2 activity.

The disclosure further provides a compound of the present disclosure, ora pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising an effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for treating a disease or disorderassociated with CDK2 activity.

In some embodiments, the disease or disorder associated with CDK2activity is a CDK2-mediated disease or disorder. In some embodiments,the disease or disorder associated with CDK2 activity is a disease ordisorder caused by CDK2 over-activity.

In some embodiments, the disease or disorder associated with CDK2activity is cancer.

In some embodiments, the cancer is selected from breast cancer, ovariancancer, bladder cancer, uterine cancer, prostate cancer, lung cancer,esophageal cancer, head and neck cancer, colorectal cancer, kidneycancer, liver cancer, pancreatic cancer, stomach cancer, melanoma andthyroid cancer.

In some embodiments, the cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is breast cancer. In some embodiments,the breast cancer is a breast cancer selected fromER-positive/HR-positive breast cancer, HER2-negative breast cancer,ER-positive/HR-positive breast cancer, HER2-positive breast cancer,triple negative breast cancer (TNBC), inflammatory breast cancer,endocrine resistant breast cancer, trastuzumab resistant breast cancer,breast cancer with primary or acquired resistance to CDK4/CDK6inhibition, advanced breast cancer and metastatic breast cancer. In someembodiments the breast cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is ovarian cancer. In some embodiments,the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In someembodiments the ovarian cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is bladder cancer. In some embodiments,the bladder cancer is characterized by amplification or overexpressionof CCNE1 and/or CCNE2.

In some embodiments, the cancer is uterine cancer. In some embodiments,the uterine cancer is characterized by amplification or overexpressionof CCNE1 and/or CCNE2.

In some embodiments, the cancer is prostate cancer. In some embodiments,the prostate cancer is characterized by amplification or overexpressionof CCNE1 and/or CCNE2.

In some embodiments, the cancer is lung cancer. In some embodiments, thelung cancer is a lung cancer selected from non-small cell lung cancer,small cell lung cancer, squamous cell carcinoma, adenocarcinoma, andmesothelioma. In some embodiments, the lung cancer is characterized byamplification or overexpression of CCNE1 and/or CCNE2. In someembodiments, the lung cancer is CCNE1 amplified squamous cell carcinomaor CCNE1 amplified adenocarcinoma.

In some embodiments, the cancer is head and neck cancer. In someembodiments, the head and neck cancer is characterized by amplificationor overexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is colorectal cancer. In someembodiments, the colorectal cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is kidney cancer. In some embodiments,the kidney cancer is renal cell carcinoma (RCC). In some embodiments,the kidney cancer is characterized by amplification or overexpression ofCCNE1 and/or CCNE2.

In some embodiments, the cancer is liver cancer. In some embodiments,the liver cancer is hepatocellular carcinoma (HCC). In some embodiments,the liver cancer is characterized by amplification or overexpression ofCCNE1 and/or CCNE2.

In some embodiments, the cancer is pancreatic cancer. In someembodiments, the pancreatic cancer is characterized by amplification oroverexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is stomach cancer. In some embodiments,the stomach cancer is characterized by amplification or overexpressionof CCNE1 and/or CCNE2.

In some embodiments, the cancer is melanoma. In some embodiments, themelanoma is characterized by amplification or overexpression of CCNE1and/or CCNE2. CDK2 expression is regulated by essential melanocytictranscription factor MITF. It has been found that CDK2 depletionsuppresses the growth of melanoma (Du et al., Cancer Cell. 2004December; 6(6): 565-576)

In some embodiments, the cancer is thyroid cancer. In some embodiments,the thyroid cancer is characterized by amplification or overexpressionof CCNE1 and/or CCNE2.

In some embodiments, the disease or disorder associated with CDK2activity is a myeloproliferative disorder.

In some embodiments, the disease or disorder associated with CDK2activity is a neurodegenerative disease or disorder. In someembodiments, the neurodegenerative disease or disorder is Alzheimer'sdisease (AD). It has been reported that neuronal cell death in subjectssuffering from AD is preceded by cell cycle events. Inhibition of one ormore CDKs can inhibit cell cycle events and therefore stave off neuronalcell death (Yang et al., J Neurosci. 2003 Apr. 1; 23(7):2557-2563).

In some embodiments, the disease or disorder associated with CDK2activity is a liver disease.

In some embodiments, the disease or disorder associated with CDK2activity is liver fibrosis. It has been reported that CCNE1 knockoutmice do not develop liver fibrosis upon exposure to pro-fibrotic toxinCCl₄, suggesting that liver fibrosis can be treated via administrationof a CDK2 inhibitor (Nevzorova, et al., Hepatology. 2012 September;56(3): 1140-1149.)

In some embodiments, the disease or disorder associated with CDK2activity is Cushing disease. Pituitary cyclin E/E2F1 signaling is amolecular mechanism underlying neuroendocrine regulation of thehypothalamic-pituitary-adrenal axis, and therefore provides asubcellular therapeutic target for CDK2 inhibitors of pituitaryACTH-dependent hypercortisolism, also known as Cushing disease (Liu, etal., J Clin Endocrinol Metab. 2015 July; 100(7): 2557-2564).

In some embodiments, the disease or disorder associated with CDK2activity is a kidney disease.

In some embodiments, the disease or disorder associated with CDK2activity is polycystic kidney disease. It has been reported thatCDK2/CDK5 inhibitor roscovitine yields effective arrest of cystic kidneydisease in mouse models of polycystic kidney disease (Bukanov, et al.,Nature. 2006 Dec. 14; 444(7121):949-52).

In some embodiments, the disease or disorder associated with CDK2activity is an autoimmune disorder. CDK2 ablation has been shown topromote immune tolerance by supporting the function of regulatory Tcells (Chunder et al., J Immunol. 2012 Dec. 15; 189(12):5659-66).

In some embodiments, the disease or disorder associated with CDK2activity is an inflammatory disorder. Cyclin E ablation has been shownto attenuate hepatitis in mice, while p27 knockout mice displayexacerbation of renal inflammation (Ehedego et al., Oncogene. 2018 June;37(25):3329-3339; Ophascharoensuk et al., Nat Med. 1998 May;4(5):575-80). In some embodiments, the inflammatory disorder ishepatitis.

In some embodiments, the compounds and compositions of the presentdisclosure are useful as male contraceptives. Based on the finding thatmale CDK2 knockout mice are sterile, CDK2 inhibitors have been studiedas possible male contraceptives (Faber, et al., Biol Reprod. 2020August; 103(2): 357-367). In some embodiments, the present disclosureprovides a method of reducing male fertility comprising administering toa patient in need thereof, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising an effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this disclosure. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present disclosure provides a method oftreating a disclosed disease or condition comprising administering to apatient in need thereof an effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof andco-administering simultaneously or sequentially an effective amount ofone or more additional therapeutic agents, such as those describedherein. In some embodiments, the method includes co-administering oneadditional therapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents that the compounds of the present disclosure may alsobe combined with include, without limitation: endocrine therapeuticagents, chemotherapeutic agents and other CDK inhibitory compounds.

In some embodiments, the present disclosure provides a method oftreating a disclosed disease or condition comprising administering to apatient in need thereof an effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof andco-administering simultaneously or sequentially an effective amount ofan endocrine therapeutic agent.

In some embodiments, the present disclosure provides a method oftreating a disclosed disease or condition comprising administering to apatient in need thereof an effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof andco-administering simultaneously or sequentially an effective amount ofone or more additional CDK inhibitory compounds. In some embodiments,the CDK inhibitory compounds are CDK4 or CDK4/CDK6 inhibitors.

In some embodiments, the present disclosure provides a method oftreating a disclosed disease or condition comprising administering to apatient in need thereof an effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof andco-administering simultaneously or sequentially an effective amount of achemotherapeutic agent. In some embodiments, the chemotherapeutic agentis a taxane. In some embodiments, the chemotherapeutic agent is aplatinum agent. In some embodiments, the chemotherapeutic agent istrastuzumab.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this disclosure. For example, a combination ofthe present disclosure may be administered with another therapeuticagent simultaneously or sequentially in separate unit dosage forms ortogether in a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this disclosure will be no more than the amount that would normallybe administered in a composition comprising that therapeutic agent asthe only active agent. Preferably the amount of additional therapeuticagent in the presently disclosed compositions will range from about 50%to 100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

One or more other therapeutic agent may be administered separately froma compound or composition of the present disclosure, as part of amultiple dosage regimen. Alternatively, one or more other therapeuticagents may be part of a single dosage form, mixed together with acompound of this disclosure in a single composition. If administered asa multiple dosage regime, one or more other therapeutic agent and acompound or composition of the present disclosure may be administeredsimultaneously, sequentially or within a period of time from oneanother, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. Insome embodiments, one or more other therapeutic agent and a compound orcomposition the present disclosure are administered as a multiple dosageregimen within greater than 24 hours a parts.

In one embodiment, the present disclosure provides a compositioncomprising a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents. The therapeuticagent may be administered together with a provided compound or apharmaceutically acceptable salt thereof, or may be administered priorto or following administration of a provided compound or apharmaceutically acceptable salt thereof. Suitable therapeutic agentsare described in further detail below. In certain embodiments, aprovided compound or a pharmaceutically acceptable salt thereof may beadministered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16hours, 17 hours, or 18 hours before the therapeutic agent. In otherembodiments, a provided compound or a pharmaceutically acceptable saltthereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

EXAMPLES

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the general procedures providedherein. It will be appreciated that, although the general methods depictthe synthesis of certain compounds of the present disclosure, thegeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

General Procedures

Abbreviations: Chloroform-d (deuterated chloroform); DMSO-d₆ (deuterateddimethylsulfoxide); Boc (tert-butoxycarbonyl); Boc₂O (di-tert-butyldicarbonate); DMF (N,N-dimethylformamide); NMP(1-methyl-2-pyrrolidinone); DMSO (dimethylsulfoxide); PE (petroleumether); EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide); ESI(electrospray atmospheric pressure ionization); TEA (tri ethyl amine);TFA (trifluoroacetic acid); dioxane (1,4-dioxane); THF(tetrahydrofuran); EtOAc (ethyl acetate); g (gram); h (hour); nm(nanometer); ¹H NMR (proton nuclear magnetic resonance); Hz (hertz);LCMS (liquid chromatography-mass spectrometry); MS (mass spectrometry);mg (milligrams); MHz (megahertz); min (minutes); mL (millilitres), mmol(millimoles); ppm (parts per million); R_(t) (retention time); RT (roomtemperature); TLC (thin layer chromatography); v/v (volume/volume); m/z(mass charge ratio); HCl (hydrochloric acid); KOAc (potassium acetate);NaOAc (sodium acetate); Pd/C (palladium on activated carbon); n-BuLi(n-butyllithium); MeI (iodomethane); EtI (iodoethane); LiHMDS (lithiumbis(trimethylsilyl)amide); NaHMDS (sodium bis(trimethylsilyl)amide);TMSOI (trimethyl sulfoxonium iodide); TMSCHN₂(trimethylsilyldiazomethane); LDA (lithium diisopropylamide); DIAD(diisopropyl azodicarboxylate); DEAD (diethyl azodicarboxylate); DBAD(di-tert-butyl azodicarboxylate); TMSCF₃(Trimethyl(trifluoromethyl)silane); X-Phos(2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl); NCS(N-chlorosuccinimide); NBS (N-bromosuccinimide); SEMCl(2-(trimethylsilyl)ethoxymethyl chloride); AIBN(2,2′-azobis(isobutyronitrile)); CO (carbon monoxide); DIPEA or DIEA(N,N-diisopropylethylamine); TBAF (tetrabutylammonium fluoride); TBAI(tetrabutylammonium iodide); DAST (diethylaminosulfur trifluoride); MW(microwave); Pd(PPh₃)₄ (tetrakis(triphenylphosphine)palladium);Pd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium); Pd(dppf)Cl₂([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium); NaH (sodiumhydride); PPh₃ (triphenylphosphine); HATU(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); TBSCl (tert-butyldimethylchlorosilane); ee(enantiomeric excess); NiCl₂(dme) (dichloro(dimethoxyethane)nickel);HOBt (hydroxybenzotriazole); DCM (dicloromethane); DMA(dimethylacetamide); prep-TLC (preparative thin layer chromatography),prep-HPLC (preparative HPLC); DEA (diethylamine); CbzCl (benzylchloroformate); ACN (acetonitrile), DCC (dicyclohexylcarbodiimide), HOSu(N-hydroxysuccinimide); quant. (quantitative yield); MTBE (methyltert-butyl ether); DIBAL-H (diisobutylaluminium hydride); DCE(1,2-dichloro ethane); DMAP (4-(dimethylamino)pyridine); IPA (isopropylalcohol); LDA (lithium diisopropylamide); TBN (tert-butyl nitrite);PMBCl (4-methoxybenzyl chloride); CAN (ceric ammonium nitrate); CDI(N,N′-carbonyldiimidazole); FmocOSu(N-(9H-fluoren-9-ylmethoxycarbonyloxy)succinimide).

Materials and Methods

NMR: ¹H NMR spectra were recorded at 400 MHz using a Bruker AVANCE 400MHz spectrometer. Data for ¹H are reported as chemical shift (ppm) andmultiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

LCMS (Shimadzu 3 min method):

-   -   LC: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector.        Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6×50 mm column. Mobile        phase: A: 0.05% formic acid in water (v/v), B: 0.05% formic acid        in MeCN (v/v). Acquire time: 3 min. LC gradient: hold 15% B for        0.28 min; then 15% to 90% in 2.1 min; then 90% to 100% in 0.01        min; then hold 100% for 0.3 min; then 100% to 15% in 0.01 min;        hold at 15% for 0.3 min. Flow Rate: 1.5 mL/min at 25° C.        Detection wavelength: 214 nm, 254 nm.    -   MS: 2020, Quadrupole LC/MS, Ion Source: API-ESI, TIC: 100˜900        m/z, Drying gas flow: 15 L/min, Nebulizer pressure: 1.5 L/min,        Drying gas temperature: 250° C., Vcap: 4500V.

LC-MS (Shimadzu 5 min method):

-   -   LC: Shimadzu LC-20AD series, Binary Pump, Diode Array Detector.        Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6×50 mm column. Mobile        phase: A: 0.05% formic acid in water (v/v), B: 0.05% formic acid        in MeCN (v/v). Acquire time: 5 min. LC gradient: hold 15% B for        0.5 min; then 15% to 85% in 3.5 min; then 85% to 100% in 0.01        min; then hold 100% for 0.49 min; then 100% to 15% in 0.01 min;        hold at 15% for 0.49 min. Flow Rate: 1 mL/min at 25° C.        Detection wavelength: 214 nm, 254 nm.    -   MS: 2020, Quadrupole LC/MS, Ion Source: API-ESI, TIC: 100˜900        m/z, Drying gas flow: 15 L/min, Nebulizer pressure: 1.5 L/min,        Drying gas temperature: 250° C., Vcap: 4500V.

LC-MS (Agilent 5 min method):

-   -   LC: Agilent Technologies 1290 series, Binary Pump, Diode Array        Detector. Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6×50 mm        column. Mobile phase: A: 0.05% formic acid in water (v/v), B:        0.05% formic acid in MeCN (v/v). Acquire time: 5 min. LC        gradient: hold 10% B for 0.5 min; then 10% to 90% in 3.5 min;        then 90% to 100% in 0.01 min; then hold 100% for 0.49 min; then        100% to 10% in 0.01 min; hold at 10% for 0.49 min. Flow Rate: 1        mL/min at 25° C. Detection wavelength: 214 nm, 254 nm.    -   MS: G6120A, Quadrupole LC/MS, Ion Source: API-ESI, TIC: 70˜1000        m/z, Fragmentor: 70, Drying gas flow: 12 L/min, Nebulizer        pressure: 36 psi, Drying gas temperature: 350° C., Vcap: 3000V.

Preparative HPLC Generic Methods:

-   -   HPLC Instruments: Shimadzu 20AP UV detector: SPD-20A. UV        wavelength: 214 nm and 254 nm.    -   Condition 1: Mobile phase A: water with 0.1% trifluoroacetic        acid; Mobile phase B: methanol.    -   Condition 2: Mobile phase A: water with 0.1% trifluoroacetic        acid; Mobile phase B: acetonitrile.    -   Column: Agilent 10 Prep-C18 250×21.2 mm. Column temperature:        Ambient    -   LC gradient: 20% to 85% in 20 min; then 85% to 100% in 0.01 min;        then hold 100% for 5 min; then 100% to 20% in 0.01 min; hold at        20% for 5 min.    -   LC Flow rate: 20 mL/min binary pump.

Example 1: Synthesis of Precursor Compounds and Intermediates Synthesisof Int-1 and Int-2

Step 1: 1-(tert-butyl) 3-ethyl 4-hydroxypyrrolidine-1,3-dicarboxylate

To a solution of 1-(tert-butyl) 3-ethyl4-oxopyrrolidine-1,3-dicarboxylate (30.0 g, 0.117 mol) in MeOH (500 mL)was added NaBH₃CN (8.04 g, 0.128 mol). Aqueous HCl (1M, 110 mL) wasadded dropwise with stirring maintaining the pH at ˜3-4. When theaddition was complete the reaction was stirred for 5 h and extractedwith EtOAc three times. The combined organic layers were washed withaqueous NaHCO₃, brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude residue was purified by column chromatography (20% EtOAc/PE) togive the product (27.0 g, 89.4%) as a colourless oil. LCMS m/z=260.1[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 4.57-4.49 (m, 1H), 4.17 (dq, J=7.2,1.6 Hz, 2H), 3.78-3.41 (m, 3H), 3.37-2.64 (m, 3H), 1.44 (app d, J=1.4Hz, 9H), 1.32-1.19 (m, 3H).

Step 2: 1-(tert-butyl) 3-ethyl 2,5-dihydro-1H-pyrrole-1,3-dicarboxylate

To a solution of 1-(tert-butyl) 3-ethyl4-hydroxypyrrolidine-1,3-dicarboxylate (27.0 g, 0.104 mol) and PPh₃(32.8 g, 0.125 mol) in dry toluene (300 mL) at 0° C. was added DIAD(25.3 g, 0.125 mol) dropwise. The mixture was allowed to warm to roomtemperature and stirred overnight. The solvent was removed under vacuumand the residue purified by column chromatography (10% EtOAc/PE) to givethe product (19.0 g, 76.4%) as a colourless oil. ¹H NMR (400 MHz,DMSO-d₆) δ 6.77 (dt, J=13.4, 1.9 Hz, 1H), 4.23-4.07 (m, 6H), 1.41 (d,J=2.3 Hz, 9H), 1.22 (t, J=7.1 Hz, 3H).

Step 3: 1-(tert-butyl) 3-ethyl4-(1-cyano-2-ethoxy-2-oxoethyl)pyrrolidine-1,3-dicarboxylate

To a solution of 1-(tert-butyl) 3-ethyl2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (19.0 g, 0.079 mol) and ethyl2-cyanoacetate (17.8 g, 0.157 mol) in DMF (250 mL) was added KOH (8.83g, 0.158 mol). The mixture was stirred for 4 h, then extracted withEtOAc three times. The combined organic layers were washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The crude waspurified by column chromatography (30% EtOAc/PE) to give the product(19.8 g, 71%) as a colourless oil. 1H NMR (400 MHz, CD₃OD) δ 4.38-4.19(m, 4H), 3.85-3.38 (m, 6H), 3.19-3.09 (m, 1H), 1.54-1.50 (m, 9H),1.42-1.23 (m, 6H).

Step 4: 2-(tert-butyl) 7-ethyl4-oxooctahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate

To a solution of 1-(tert-butyl) 3-ethyl4-(1-cyano-2-ethoxy-2-oxoethyl)pyrrolidine-1,3-dicarboxylate (19.8 g,0.056 mol) in EtOH (250 mL) was added Raney Ni (5 g). The resultingmixture was stirred under an atmosphere of H₂ overnight. The reactionmixture was filtered through a pad of celite and the filtrate wasconcentrated in vacuo. The crude was purified by column chromatography(50% EtOAc/PE) to give the product (13.9 g, 79%) as a colourless oil. ¹HNMR (400 MHz, CD₃OD) δ 4.25-4.14 (m, 2H), 3.84-3.33 (m, 6H), 3.28-2.67(m, 3H), 1.46 (d, J=3.7 Hz, 9H), 1.28 (dt, J=7.2, 3.0 Hz, 3H).

Step 5: 2-(tert-butyl) 7-ethyloctahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate (Int-1) and(Int-2)

To a solution of 2-(tert-butyl) 7-ethyl4-oxooctahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate (13.9 g,0.044 mol) and PhSiH₃ (12.11 g, 0.112 mol) in dry toluene (300 mL) wasadded NiCl₂(dme) (1.23 g, 0.006 mol). The mixture was heated at refluxunder N₂ overnight. The solvent was removed and the residue taken up inEtOAc. The organic phase was washed with aqueous NaHCO₃ and brine, driedover Na₂SO₄ and concentrated in vacuo. The crude residue was purified bycolumn chromatography (2.5% MeOH/DCM) to give Int-1 (4.0 g, 30%) as thefirst eluting diastereomer and Int-2 (2.1 g, 14%) as the second elutingdiastereomer. Int-1: LCMS m/z=299.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ4.16-4.04 (m, 2H), 3.36-3.18 (m, 4H), 3.10-3.02 (m, 1H), 2.86-2.75 (m,2H), 2.69-2.57 (m, 1H), 2.47-2.39 (m, 1H), 2.38-2.28 (m, 2H), 1.43-1.37(m, 9H), 1.24-1.17 (m, 3H). Int-2: LCMS m/z=299.1 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ 4.21-4.10 (m, 2H), 3.46-3.34 (m, 2H), 3.30-3.25 (m, 1H),3.18-3.00 (m, 2H), 2.95-2.68 (m, 4H), 2.41-2.22 (m, 2H), 1.50-1.43 (m,9H), 1.30-1.23 (m, 3H).

Alternative synthesis of 1-(tert-butyl) 3-ethyl4-(1-cyano-2-ethoxy-2-oxoethyl)pyrrolidine-1,3-dicarboxylate

Step 1: 1-(tert-butyl) 3-ethyl4-(1-cyano-2-ethoxy-2-oxoethylidene)pyrrolidine-1,3-dicarboxylate

A mixture of 1-(tert-butyl) 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate(20.0 g, 0.078 mol), ethyl 2-cyanoacetate (8.8 g, 0.093 mol) andpiperidine (20.0 g, 0.078 mol) was stirred for 2 days under N₂. Theresulting mixture was concentrated in vacuo and the crude purified bycolumn chromatography (6% EtOAc/PE) to afford the product (8.11 g,29.6%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 4.66-4.49 (m, 1H),4.46-3.60 (m, 8H), 1.53-1.44 (m, 9H), 1.39-1.22 (m, 6H).

Step 2: 1-(tert-butyl) 3-ethyl4-(1-cyano-2-ethoxy-2-oxoethyl)pyrrolidine-1,3-dicarboxylate

To a solution of InCl₃ (204 mg, 0.92 mmol) and NaBH₄ (387 mg, 10.2 mmol)in acetonitrile (10 mL) was added a solution of 1-(tert-butyl) 3-ethyl4-(1-cyano-2-ethoxy-2-oxoethylidene)pyrrolidine-1,3-dicarboxylate (2.4g, 6.8 mmol) in acetonitrile (15 mL). The mixture was stirred at roomtemperature for 3 h. The reaction mixture was quenched with water andextracted with EtOAc three times. The combined organic layers werewashed with water, brine, and dried over Na₂SO₄. The solvent was removedand the crude purified by column chromatography (30% EtOAc/PE) to affordthe product (1.5 g, 62.2%) as a colorless oil. LCMS m/z=299.1[M−tBu+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 4.39-4.17 (m, 4H), 3.85-3.65 (m,2H), 3.64-3.35 (m, 4H), 3.18-3.05 (m, 1H), 1.55-1.48 (m, 9H), 1.41-1.28(m, 6H).

Synthesis of (S)-2-amino-N-methyl-5-phenylpentanamide

Step 1: tert-butyl(S)-(1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamate

A solution of (S)-2-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid(3.0 g, 10.2 mmol), HATU (5.83 g, 15.3 mmol) and DIEA (5.3 g, 40.8 mmol)in DMF (15 mL) was stirred at room temperature for 30 min Methylaminehydrochloride (830 mg, 12.3 mmol) was then added and the mixture stirredfor another 6 h. Water was added and the precipitate collected byfiltration, then washed with water and dried under vacuum to afford theproduct (2.1 g, 67%) as a white solid. LCMS m/z=307.2 [M+H]⁺.

Step 2: (S)-2-amino-N-methyl-5-phenylpentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamate (2.1 g, 6.85mmol) in DCM (20 mL) was added HCl (4M in dioxane, 20 mL) and themixture was stirred at room temperature for 2 h. The solvent was removedto afford the product (1.65 g, quant.) as white solid. LCMS m/z=207.1[M+H]⁺.

Synthesis of (S)-2-amino-3-(1H-indol-3-yl)-N-methylpropanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N-methyl-5-phenylpentanamide, starting with(tert-butoxycarbonyl)-L-tryptophan in place of(S)-2-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid. LCMSm/z=218.0 [M+H]⁺.

Synthesis of (R)-2-amino-N-methyl-3-phenylpropanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N-methyl-5-phenylpentanamide, starting with(tert-butoxycarbonyl)-D-phenylalanine in place of(S)-2-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid. LCMSm/z=179.1 [M+H]⁺.

Synthesis of (R)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N-methyl-5-phenylpentanamide, starting with(tert-butoxycarbonyl)-D-tyrosine in place of(S)-2-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid. LCMSm/z=195.2 [M+H]⁺.

Synthesis of (R)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N-methyl-5-phenylpentanamide, starting with(tert-butoxycarbonyl)-L-phenylalanine in place of(S)-2-((tert-butoxycarbonyl)amino)-5-phenylpentanoic acid. LCMSm/z=179.2 [M+H]⁺.

Synthesis of 4-(2-cyclopropylethoxy)-3-methoxybenzoic acid

Step 1: methyl 4-(2-cyclopropylethoxy)-3-methoxybenzoate

To a solution of methyl 4-hydroxy-3-methoxybenzoate (100 mg, 0.55 mmol)in dry THF (3 mL) was added 2-cyclopropylethan-1-ol (57 mg, 0.66 mmol)and PPh₃ (288 mg, 1.10 mmol). After stirring at 0° C. for 10 min, DIAD(166 mg, 082 mmol) was added and the reaction mixture was allowed towarm to room temperature and stirred for another 2 h. Water was addedand the aqueous extracted with EtOAc three times. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. The solventwas removed and the residue purified by prep-TLC (50% PE/EtOAc) toafford methyl 4-(2-cyclopropylethoxy)-3-methoxybenzoate (80 mg, 59%) asa white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.63 (dd, J=8.4, 2.0 Hz, 1H),7.54 (d, J=2.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 4.13 (t, J=6.5 Hz, 2H),3.87 (d, J=1.5 Hz, 6H), 1.71 (q, J=6.7 Hz, 2H), 0.96-0.84 (m, 1H),0.53-0.45 (m, 2H), 0.18-0.11 (m, 2H).

Step 2: 4-(2-cyclopropylethoxy)-3-methoxybenzoic acid 0

To a solution of methyl 4-(2-cyclopropylethoxy)-3-methoxybenzoate (80mg, 0.32 mmol) in MeOH (2 mL) was added aqueous NaOH (1M, 0.5 mL). Theresulting mixture was stirred for 3 h. The residue obtained afterconcentration was diluted with water and the pH adjusted to ˜1 byaddition of 1M HCl. The aqueous layer was extracted with EtOAc threetimes and the combined organic layers were washed with water, brine anddried over Na₂SO₄. 4-(2-cyclopropylethoxy)-3-methoxybenzoic acid (50 mg,67%) was obtained after removal of the solvent as a white solid. ¹H NMR(400 MHz, CD₃OD) δ 7.65 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H),7.01 (d, J=8.4 Hz, 1H), 4.13 (t, J=6.6 Hz, 2H), 3.87 (s, 3H), 1.71 (q,J=6.7 Hz, 2H), 0.89 (td, J=7.3, 4.0 Hz, 2H), 0.55-0.45 (m, 1H),0.22-0.11 (m, 2H).

Synthesis of 2-phenyloxazole-5-carboxylic acid

Step 1: N-(prop-2-yn-1-yl)benzamide

To a solution of benzoyl chloride (1.0 g, 7.14 mmol) and TEA (2.7 g,26.7 mmol) in DCM (5 mL) was added prop-2-yn-1-amine (0.43 g, 7.80 mmol)dropwise. The mixture was stirred at r.t. overnight. The resultingmixture was extracted with EtOAc three times. The combined organiclayers were washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo. The obtained residue was purified by columnchromatography (10% EtOAc/PE) to afford N-(prop-2-yn-1-yl)benzamide(0.80 g, 71.4%) as a colourless solid. LCMS m/z=160.1 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 8.92 (t, J=5.6 Hz, 1H), 7.90-7.80 (m, 2H),7.58-7.42 (m, 3H), 4.05 (dd, J=5.6, 2.5 Hz, 2H), 3.11 (t, J=2.5 Hz, 1H).

Step 2: 2-phenyloxazole-5-carbonitrile

To a solution of N-(prop-2-yn-1-yl)benzamide (350 mg, 2.201 mmol) inacetonitrile (5 mL) was added Ph₃PauNTf₂ (23.2 mg, 0.110 mmol), t-BuONO(680.1 mg, 6.603 mmol), N-Hydroxyphthalimide (107.6 mg, 0.660 mmol),bis(2,4-pentanedionato)cobalt (42.2 mg, 0.165 mmol) and magnesium oxide(266.1 mg, 6.603 mmol). The mixture was heated at 50° C. for 3 h. Thesolvent was removed under vacuum and the residue was purified byprep-TLC (6.6% MeOH/DCM) to give 2-phenyloxazole-5-carbonitrile (34 mg,9.1%) as a colorless oil. LCMS m/z=171.1 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.42 (s, 1H), 8.12-8.03 (m, 2H), 7.69-7.57 (m, 3H).

Step 3: 2-phenyloxazole-5-carboxylic acid

To a solution of 2-phenyloxazole-5-carbonitrile (35 mg, 0.205 mmol) in amixture of DMSO (1 mL) and H₂O (0.5 mL) was added NaOH (24.6 mg, 0.615mmol). The mixture was heated at 100° C. for 3 h. After pH was adjustedto ˜1 with adding of 1M HCl, the aqueous was extracted with EtOAc threetimes. 2-phenyloxazole-5-carboxylic acid (34 mg, 87.2%) was obtainedafter removal of the solvent as a white solid. LCMS m/z=190.0 [M+H]⁺.

Synthesis of 3-methoxy-4-sulfamoylbenzoic acid

To a solution of 2-methoxy-4-methylbenzenesulfonamide (1.00 g, 4.97mmol) in H₂O (5 mL) was added NaHCO₃ (0.34 g, 3.98 mmol) and KMnO₄ (3.14g 19.88 mmol). The resulting mixture was stirred at 100° C. overnight.After filtration, the filtrate was acidified by adding of 1M HCl untilpH to ˜2 then extracted by EtOAc three times. The combined organiclayers were washed with water, brine, dried over Na₂SO₄.3-methoxy-4-sulfamoylbenzoic acid (200 mg, 17%) was obtained afterremoval of the solvent as a white solid. LCMS m/z=232.1 [M+H]⁺.

Synthesis of 4-(cyclopropanecarboxamido)-3-methoxybenzoic acid

Step 1: methyl 4-(cyclopropanecarboxamido)-3-methoxybenzoate

To a solution of methyl 4-amino-3-methoxybenzoate (500 mg, 2.76 mmol) inDCM (5 mL) at 0° C. was added TEA (836 mg, 8.26 mmol) andcyclopropanecarbonyl chloride (346 mg, 3.31 mmol). The resulting mixturewas stirred at 0° C. for 1 h. The residue after concentration waspurified by column chromatography (30% EtOAc/PE) to afford methyl4-(cyclopropanecarboxamido)-3-methoxybenzoate (400 mg, 58.2%) as a whitesolid. LCMS m/z=250.1 [M+H]⁺.

Step 2: 4-(cyclopropanecarboxamido)-3-methoxybenzoic acid

To a solution of methyl 4-(cyclopropanecarboxamido)-3-methoxybenzoate(150.0 mg, 0.60 mmol) in a mixture of THF (2 mL) and H₂O (2 mL) wasadded LiOH (43 mg, 1.8 mmol). The resulting mixture was stirred at roomtemperature for 3 h. The pH of reaction mixture was adjusted to ˜2 byadding of 1M HCl then extracted with EtOAc three times. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄.4-(Cyclopropanecarboxamido)-3-methoxybenzoic acid (140 mg, 98.9%) wasobtained after removal of the solvent as a white solid. LCMS m/z=236.0[M+H]⁺.

Synthesis of 3-methoxy-4-(methylsulfonamido)benzoic acid

Step 1: methyl 3-methoxy-4-(methylsulfonamido)benzoate

To a solution of methyl 4-amino-3-methoxybenzoate (500 mg, 2.7 mmol) inDCM (5 mL) and pyridine (0.5 mL) was added methanesulfonyl chloride (720mg, 4.2 mmol) and DMAP (20 mg, 0.135 mmol) at 0° C. The resultingmixture was stirred for 4 h. Water was added and the aqueous extractedwith EtOAc three times. The combined organic layers were washed withwater, brine and dried over Na₂SO₄. The residue after concentration waspurified by column chromatography (2% MeOH/DCM) to afford methyl3-methoxy-4-(methylsulfonamido)benzoate (680 mg, 97%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J=8.4, 1.7 Hz, 1H), 7.58 (d, J=1.4Hz, 2H), 7.12 (s, 1H), 3.92 (d, J=13.0 Hz, 6H), 3.03 (s, 3H).

Step 2: 3-methoxy-4-(methylsulfonamido)benzoic acid

To a solution of methyl 3-methoxy-4-(methylsulfonamido)benzoate (680 mg,2.62 mmol) in MeOH (10 mL) and THF (5 mL) was added LiOH (275 mg, 6.55mmol). The mixture was stirred for 2 h. The solvent was removed undervacuum and the residue obtained was diluted with water and the pHadjusted to ˜1 by addition of 1M HCl. The aqueous layer was extractedwith EtOAc three times. The combined organic layers were washed withwater and brine, dried over Na₂SO₄ and the solvent removed to affordmethyl 3-methoxy-4-(methylsulfonamido)benzoate (563 mg, 87.8%) as awhite solid. ¹H NMR (400 MHz, CD₃OD) δ 6.83 (t, J=1.0 Hz, 2H), 6.77-6.69(m, 1H), 3.14 (d, J=0.9 Hz, 3H), 2.20 (d, J=1.0 Hz, 3H).

Synthesis of (3-aminopiperidin-1-yl)(phenyl)methanone hydrochloride

Step 1: tert-butyl (1-benzoylpiperidin-3-yl)carbamate

To a solution of tert-butyl piperidin-3-ylcarbamate (300 mg, 1.5 mmol)in DMA (5 mL) was added benzoic acid (275.0 mg, 28.2 mmol), EDCI (430.7mg, 2.25 mmol), HOBt (243 mg, 1.85 mmol) and DIPEA (232.3 mg, 1.85mmol). The resulting mixture was stirred overnight. Water was added intothe reaction mixture then extracted with EtOAc three times. The combinedorganic layers were washed with water, brine, dried over Na₂SO₄. Theresidue after concentration was purified by column chromatography (10%EtOAc/PE) to afford tert-butyl (1-benzoylpiperidin-3-yl)carbamate (367mg, 81%) as a white solid. LCMS m/z=305.2 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ 7.54-7.31 (m, 5H), 3.46 (d, J=58.1 Hz, 2H), 3.05 (d, J=47.2 Hz,2H), 2.11-1.68 (m, 3H), 1.66-1.20 (m, 12H).

Step 2: (3-aminopiperidin-1-yl)(phenyl)methanone hydrochloride

To a solution of tert-butyl (1-benzoylpiperidin-3-yl)carbamate (367 mg,1.2 mmol) in DCM (5 mL) was added HCl (4M in dixoane, 3 mL). Theresulting mixture was stirred for 4 h. The solvent was removed to afford(3-aminopiperidin-1-yl)(phenyl)methanone hydrochloride (390 mg, quant.)LCMS m/z=205.1 [M+H]⁺.

Synthesis of 1-(3-aminopiperidin-1-yl)-2-phenylethan-1-one hydrochloride

Step 1: tert-butyl (1-(2-phenylacetyl)piperidin-3-yl)carbamate

To a solution of tert-butyl piperidin-3-ylcarbamate (200 mg, 1.0 mmol)in DMA (5 mL) was added 2-phenylacetic acid (204.0 mg, 1.5 mmol), EDCI(287.1 mg, 1.5 mmol), HOBt (162.0 mg, 1.2 mmol) and DIPEA (154.9 mg, 1.2mmol). The resulting mixture was stirred overnight. Water was added intothe reaction mixture then extracted with EtOAc three times. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Thesolvent was removed and the residue purified by column chromatography(10% EtOAc/PE) to afford tert-butyl(1-(2-phenylacetyl)piperidin-3-yl)carbamate (234 mg, 74%) as a whitesolid. LCMS m/z=319.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.17 (m,5H), 3.94-3.66 (m, 4H), 3.44-3.34 (m, 1H), 3.19-3.05 (m, 2H), 2.01-1.66(m, 1H), 1.57-1.36 (m, 12H).

Step 2: 1-(3-aminopiperidin-1-yl)-2-phenylethan-1-one hydrochloride

To a solution of tert-butyl (1-(2-phenylacetyl)piperidin-3-yl)carbamate(367 mg, 1.2 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 3 mL).The resulting mixture was stirred for 4 h. The solvent was removed toafford 1-(3-aminopiperidin-1-yl)-2-phenylethan-1-one hydrochloride (240mg, quant.) LCMS m/z=219.1 [M+H]⁺.

Synthesis of (S)-2-amino-N-methyl-5-(pyridin-2-yl)pentanamide

Step 1: tert-butyl (S)-(1-(methylamino)-1-oxopent-4-yn-2-yl) carbamate

To a solution of methanamine hydrochloride (950 mg, 14.07 mmol) in DMF(20 mL) was added (S)-2-((tert-butoxycarbonyl)amino)pent-4-ynoic acid(2.0 g, 9.38 mmol), EDCI (2.7 g, 14.07 mmol), HOBt (1.9 g, 14.07 mmol)and DIPEA (3.6 g, 28.14 mmol). The resulting mixture was stirred at roomtemperature for 4 h. Water was added and the aqueous extracted withEtOAc three times. The combined organic layers were washed with water,brine and dried over Na₂SO₄. The solvent was removed and the residuepurified by column chromatography (5% MeOH/DCM) to afford tert-butyl(S)-(1-(methylamino)-1-oxopent-4-yn-2-yl) carbamate (1.6 g, 76%) as awhite solid. ¹H NMR (400 MHz, CD₃OD) δ 4.18 (t, J=6.7 Hz, 1H), 2.74 (s,3H), 2.67-2.60 (m, 1H) 2.58-2.49 (m, 1H), 2.36 (s, 1H), 1.45 (s, 9H).

Step 2: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-2-yl)pent-4-yn-2-yl) carbamate

A mixture of tert-butyl (S)-(1-(methylamino)-1-oxopent-4-yn-2-yl)carbamate (300 mg, 1.33 mmol), 2-bromopyridine (210 mg, 1.33 mmol),Pd(PPh₃)₄ (116 mg, 0.13 mmol), CsF (445 mg, 2.93 mmol), CuI (25 mg, 0.13mmol) in DMF (5 mL) was heated at 100° C. for 3 h under an atmosphere ofN2. Water was added and the aqueous extracted with EtOAc three times.The combined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed and the residue purified by prep-TLC (7%MeOH/DCM) to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-2-yl)pent-4-yn-2-yl) carbamate(142 mg, 35%) as a brown oil. LCMS m/z=304 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ 8.47 (d, J=5.4 Hz, 1H), 7.80 (tt, J=7.7, 1.2 Hz, 1H), 7.49 (d,J=7.9 Hz, 1H), 7.40-7.33 (m, 1H), 4.32 (t, J=6.6 Hz, 1H), 2.95-2.81 (m,2H), 2.76 (s, 3H), 1.44 (d, J=0.9 Hz, 9H).

Step 3: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-2-yl)pentan-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-2-yl)pent-4-yn-2-yl) carbamate(100 mg, 0.33 mmol) in MeOH (2 mL) was added Pd/C (10%, 10 mg). Theresulting mixture was stirred for 3 h under an atmosphere of H₂. Thereaction mixture was filtered through celite, the solvent removed andthe residue purified by prep-TLC (7% MeOH/DCM) to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-2-yl)pentan-2-yl)carbamate (30 mg,33%) as a colorless oil LCMS m/z=308 [M+H]⁺.

Step 4: (S)-2-amino-N-methyl-5-(pyridin-2-yl)pentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-2-yl)pentan-2-yl)carbamate (30 mg,0.098 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 1 mL). Theresulting mixture was stirred at room temperature for 3 h. The solventwas removed under reduced pressure to afford(S)-2-amino-N-methyl-5-(pyridin-2-yl)pentanamide (22 mg, quant.). LCMSm/z=208 [M+H]⁺.

Synthesis of (2R,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide

Step 1: (tert-butoxycarbonyl)-D-allothreonine

To a solution of D-allothreonine (1.0 g, 8.4 mmol) in a mixture of THFand H₂O (10 mL/2 mL) was added K₂CO₃ (2.3 g, 16.8 mmol) and Bocanhydride (2.0 g, 9.2 mmol). The resulting mixture was stirredovernight. Water was added and the aqueous extracted with EtOAc. Thecombined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed to afford(tert-butoxycarbonyl)-D-allothreonine (700 mg, 39%) as a yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 6.78 (d, J=7.7 Hz, 1H), 3.90-3.79 (m, 2H), 1.38(s, 9H), 1.08 (d, J=5.5 Hz, 3H).

Step 2: O-benzyl-N-(tert-butoxycarbonyl)-D-allothreonine

To a solution of (tert-butoxycarbonyl)-D-allothreonine (700 mg, 3.2mmol) in DMF (5.0 mL) was added NaH (270 mg, 6.7 mmol) portionwise at 0°C. After stirring for 1 h, BnBr (544 mg, 3.2 mmol) was added and thereaction mixture was stirred for another 14 h. The solvent was removedand the residue purified by RP column to affordO-benzyl-N-(tert-butoxycarbonyl)-D-allothreonine (345 mg, 35%) as awhite solid. ¹H NMR (400 MHz, CD₃OD) δ 7.38-7.23 (m, 5H), 4.63-4.51 (m,2H), 4.46 (d, J=4.9 Hz, 1H), 3.92 (p, J=6.5 Hz, 1H), 1.45 (s, 9H), 1.21(d, J=6.4 Hz, 3H).

Step 3: tert-butyl((2R,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate

To a solution of O-benzyl-N-(tert-butoxycarbonyl)-D-allothreonine (100mg, 0.32 mmol) in DMF (2 mL) was added CH₃NH₂.HCl (26 mg, 0.39 mmol),EDCI (93 mg, 0.48 mmol), HOBt (66 mg, 0.48 mmol) and DIPEA (209 mg, 1.62mmol). The resulting mixture was stirred at room temperature for 14 h.Water was added and the aqueous extracted with EtOAc. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Thesolvent was removed and the residue purified by column chromatography(1% MeOH/DCM) to afford tert-butyl((2R,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate (80 mg,80%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.35-7.21 (m, 5H), 4.52(q, J=11.5 Hz, 2H), 3.83 (t, J=6.4 Hz, 1H), 2.73 (s, 3H), 2.45-2.30 (m,1H), 1.44 (s, 9H), 1.19 (t, J=6.7 Hz, 3H).

Step 4: (2R,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide

To a solution of tert-butyl((2R,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate (80 mg,0.25 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixturewas stirred for 3 h. The solvent was removed under reduced pressure toafford (2R,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide (55 mg, quant.).This product was used directly in next step.

Synthesis of (2S,3S)-2-amino-3-(benzyloxy)-N-methylbutanamide

Made using a similar method as described for the synthesis of(2R,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide. LCMS m/z=223.1 [M+H]⁺.

Synthesis of (S)-2-amino-5-cyclopentyl-N-methylpentanamide

Step 1: tert-butyl(S)-(5-cyclopentyl-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (200 mg, 0.877 mmol)in DCM (3 mL) was added vinylcyclopentane (169 mg, 1.754 mmol) andGrubbs catalyst (150 mg, 0.17 mmol). The resulting mixture was stirredat room temperature for 12 h. Water was added and the aqueous extractedwith EtOAc. The combined organic layers were washed with water, brineand dried over Na₂SO₄. The solvent was removed and the residue purifiedby column chromatography (33% EtOAc/PE) to afford tert-butyl(S)-(5-cyclopentyl-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (58 mg,22%) as a white solid. LCMS m/z=297 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ5.61-5.17 (m, 2H), 4.05-3.84 (m, 1H), 2.72 (d, J=3.6 Hz, 3H), 2.32 (ddt,J=61.8, 14.6, 7.8 Hz, 3H), 1.81-1.52 (m, 6H), 1.44 (s, 9H), 1.34-1.24(m, 2H).

Step 2: tert-butyl(S)-(5-cyclopentyl-1-(methylamino)-1-oxopentan-2-yl)carbamate

To a solution of tert-butyl(S)-(5-cyclopentyl-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (58 mg,0.196 mmol) in MeOH (1 mL) was added 10% Pd/C (10 mg). The resultingmixture was stirred at room temperature for 3 h under an atmosphere ofH₂. The filtrate through a pad of celite was concentrated to affordtert-butyl (S)-(5-cyclopentyl-1-(methylamino)-1-oxopentan-2-yl)carbamate(50 mg, 99%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 3.97 (dd,J=9.2, 5.3 Hz, 1H), 2.73 (s, 3H), 1.87-1.47 (m, 9H), 1.44 (s, 9H),1.41-0.82 (m, 7H).

Step 3: (S)-2-amino-5-cyclopentyl-N-methylpentanamide

To a solution of tert-butyl(S)-(5-cyclopentyl-1-(methylamino)-1-oxopentan-2-yl)carbamate (50 mg,0.167 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 1 ml). Themixture was stirred at room temperature for 3 h. The mixture wasconcentrated to afford (S)-2-amino-5-cyclopentyl-N-methylpentanamide.

Synthesis of(S)-2-amino-N-methyl-5-(4-(trifluoromethyl)cyclohexyl)pentanamide

Step 1: 4-(trifluoromethyl)cyclohex-1-en-1-yl trifluoromethanesulfonate

To a solution of 4-(trifluoromethyl)cyclohexan-1-one (500 mg, 3.01 mmol)in THF (8 mL) at −78° C. was added LiHMDS (3.6 mL, 3.61 mmol) dropwiseand stirred for 30 minute. Then a solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.18 g, 3.31 mmol) in THF (1 mL) was added thereto and the mixture wasstirred at room temperature overnight. Water was added and the aqueousextracted with EtOAc. The combined organic layers were washed withwater, brine and dried over Na₂SO₄. The solvent was removed and theresidue purified by column chromatography (2% MeOH/DCM) to afford4-(trifluoromethyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (400 mg,45%). ¹H NMR (400 MHz, Chloroform-d) δ 5.81-5.76 (m, 1H), 2.55-2.39 (m,3H), 2.38-2.25 (m, 2H), 2.15 (ddt, J=13.1, 4.9, 2.5 Hz, 1H), 1.77 (dtd,J=13.0, 11.1, 6.3 Hz, 1H).

Step 2: tert-butyl((2S,E)-1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)pent-4-en-2-yl)carbamate

A mixture of 4-(trifluoromethyl)cyclohex-1-en-1-yltrifluoromethanesulfonate (250 mg, 0.838 mmol), tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (172 mg, 0.755 mmol),Pd(OAc)₂ (19 mg, 0.084 mmol) and NaHCO₃ (211 mg, 2.52 mmol) in DMF/H₂O(4 mL/1 mL) was stirred at 70° C. overnight. Water was added and theaqueous extracted with EtOAc. The combined organic layers were washedwith water, brine and dried over Na₂SO₄. The solvent was removed and theresidue purified by column chromatography (1.5% MeOH/DCM) to affordtert-butyl((2S,E)-1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)pent-4-en-2-yl)carbamate(120 mg, 38%). LCMS m/z=377 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 6.23-5.63(m, 2H), 5.56-4.80 (m, 2H), 4.12 (d, J=7.1 Hz, 1H), 2.82 (d, J=4.9 Hz,3H), 2.60-2.26 (m, 3H), 2.27-1.92 (m, 3H), 1.48-1.39 (m, 9H), 1.29-1.23(m, 2H).

Step 3: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)cyclohexyl)pentan-2-yl)carbamate

To a solution of ((2S,E)-1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)pent-4-en-2-yl)carbamate(120 mg, 0.319 mmol) in MeOH (2 mL) was added 10% Pd/C (12 mg). Theresulting mixture was stirred under H₂ overnight. The mixture wasfiltered through a pad of celite and the solvent remove from thefiltrate to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)cyclohexyl)pentan-2-yl)carbamate(100 mg, 83%). LCMS m/z=381 [M+H]⁺.

Step 4:(S)-2-amino-N-methyl-5-(4-(trifluoromethyl)cyclohexyl)pentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)cyclohexyl)pentan-2-yl)carbamate(100 mg, 0.263 mmol) in DCM (3 mL) was added TFA (3 mL). The mixture wasstirred for 3 h. The solvent was removed to afford(S)-2-amino-N-methyl-5-(4-(trifluoromethyl)cyclohexyl)pentanamide (76mg, quant.). LCMS m/z=281 [M+H]⁺

Synthesis of (S)-2-amino-5-cycloheptyl-N-methylpentanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N-methyl-5-(4-(trifluoromethyl)cyclohexyl)pentanamide,starting from cycloheptanone, in place of4-(trifluoromethyl)cyclohexan-1-one. L CMS m/z=227.1 [M+H]⁺.

Synthesis of (S)-2-amino-N,6,6-trimethylheptanamide

Step 1: tert-butyl(S,E)-(6,6-dimethyl-1-(methylamino)-1-oxohept-4-en-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (500 mg, 2.19 mmol)and 3,3-dimethylbut-1-ene (992.0 mg, 10.9 mmol) in toluene (10 mL) wasadded Hoveyda-Grubbs Catalyst 2nd Generation (274.4 mg, 0.428 mmol). Themixture was stirred at 100° C. for two days. The resulting mixture wasconcentrated in vacuo. The solvent was removed and the residue purifiedby column chromatography (25% EtOAc/PE) to afford tert-butyl(S,E)-(6,6-dimethyl-1-(methylamino)-1-oxohept-4-en-2-yl)carbamate (85.0mg, 14%) as colourless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.15 (s, 1H), 5.56(m, 1H), 5.41-5.04 (m, 1H), 2.80 (d, J=4.9 Hz, 3H), 2.54-2.22 (m, 2H),1.43 (s, 9H), 0.98 (s, 9H).

Step 2: tert-butyl(S)-(6,6-dimethyl-1-(methylamino)-1-oxoheptan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(6,6-dimethyl-1-(methylamino)-1-oxohept-4-en-2-yl)carbamate (85mg, 0.299 mmol) in MeOH (3 mL) was added Pd/C (10 mg). The mixture wasstirred under an atmosphere of H₂ for 8 h. The mixture was filteredthrough a pad of celite and the solvent removed from the filtrate toafford tert-butyl(S)-(6,6-dimethyl-1-(methylamino)-1-oxoheptan-2-yl)carbamate (76.0 mg,80%) as colourless oil. LCMS m/z=287 [M+H]⁺.

Step 3: (S)-2-amino-N,6,6-trimethylheptanamide

To a solution of tert-butyl(S)-(6,6-dimethyl-1-(methylamino)-1-oxoheptan-2-yl)carbamate (76.0 mg,0.27 mmol) in DCM (5 mL) was added HCl (4 M in dioxane, 3 mL). Theresulting mixture was stirred for 3 h. The solvent was removed to afford(S)-2-amino-N,6,6-trimethylheptanamide (80 mg, quant.). LCMS m/z=186[M+H]⁺.

Synthesis of (S)-2-amino-N,6-dimethylheptanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N,6,6-trimethylheptanamide, using 3-methylbut-1-ene andGrubbs catalyst in place of 3,3-dimethylbut-1-ene and Hoveyda-Grubbscatalyst, respectively. The solvent was removed in vacuo and the crudeproduct was used directly in the synthesis of additional compounds.

Synthesis of (S)-2-amino-5-cyclohexyl-N-methylpentanamide

Made using a similar method as described for the synthesis of(S)-2-amino-N,6,6-trimethylheptanamide, using vinylcyclohexane andGrubbs catalyst in place of 3,3-dimethylbut-1-ene and Hoveyda-Grubbscatalyst, respectively LCMS m/z=213.1 [M+H]⁺.

Synthesis of 2-amino-N-(3-phenylpropyl)acetamide

Step 1: tert-butyl (2-oxo-2-(3-phenylpropyl)amino)ethyl)carbamate

To a solution of (tert-butoxycarbonyl)glycine (500 mg, 2.85 mmol), EDCI(821 mg, 4.28 mmol) and HOBt (463 mg, 3.42 mmol) in DMA (10 mL) wasadded 3-phenylpropan-1-amine (424 mg, 3.14 mmol) and DIEA (1.11 g, 8.56mmol). The mixture was stirred at room temperature overnight. Water wasadded and the aqueous extracted with EtOAc three times. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄ andthe solvent removed in vacuo. The crude was purified by columnchromatography (2.5% MeOH/DCM) to give tert-butyl(2-oxo-2-((3-phenylpropyl)amino)ethyl)carbamate (538 mg, 64%). LCMSm/z=293.3 [M+H]⁺.

Step 2: 2-amino-N-(3-phenylpropyl)acetamide

A solution of tert-butyl (2-oxo-2-((3-phenylpropyl)amino)ethyl)carbamate(500 mg, 1.71 mmol) in HCl (4M in dioxane, 5 mL) was stirred for 1 h.The volatiles were removed in vacuo to give2-amino-N-(3-phenylpropyl)acetamide (486 mg, quant.).

Synthesis of (S)-2-amino-N-methyl-N-(3-phenylpropyl)propanamide

Made using a similar method as described for the synthesis of2-amino-N-(3-phenylpropyl)acetamide, starting fromN-methyl-3-phenylpropan-1-amine and (tert-butoxycarbonyl)-L-alanine.LCMS m/z=221.3 [M+H]⁺.

Synthesis of 2-amino-N-methyl-N-(3-phenylpropyl)acetamide Made using asimilar method as described for the synthesis of2-amino-N-(3-phenylpropyl)acetamide, starting fromN-methyl-3-phenylpropan-1-amine and (tert-butoxycarbonyl)glycine. LCMSm/z=207.2 [M+H]⁺.

Synthesis of (2S,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide

Step 1: N-(tert-butoxycarbonyl)-O-(cyclohexylmethyl)-L-threonine

To a solution of O-benzyl-N-(tert-butoxycarbonyl)-L-threonine (400 mg,1.29 mmol) in IPA (15 mL) was added Rh—Al₂O₃(5%, 50 mg). The resultingmixture was stirred overnight under H₂. The reaction mixture wasfiltered through a pad of celite, the solvent removed and the residuepurified by column chromatography (10% MeOH/DCM) to affordN-(tert-butoxycarbonyl)-O-(cyclohexylmethyl)-L-threonine (390 mg, 95.6%)as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 4.09 (d, J=2.8 Hz, 1H),4.04-3.94 (m, 1H), 3.39-3.33 (m, 1H), 3.17-3.09 (m, 1H), 1.79-1.62 (m,4H), 1.53-1.40 (m, 9H), 1.34-1.09 (m, 8H), 1.00-0.81 (m, 2H).

Step 2: tert-butyl((2S,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate

To a solution ofN-(tert-butoxycarbonyl)-O-(cyclohexylmethyl)-L-threonine (390 mg, 1.24mmol) in DMF (8 mL) was added methylamine hydrochloride (167 mg, 2.47mmol), EDCI (357 mg, 1.86 mmol), HOBt (202 mg, 1.49 mmol) and DIPEA (320mg, 2.47 mmol). The resulting mixture was stirred at room temperatureovernight. Water was added and the aqueous extracted with EtOAc threetimes. The combined organic layers were washed with water, brine anddried over Na₂SO₄. The solvent was removed and the residue purified bycolumn chromatography (1.9% MeOH/DCM) to afford tert-butyl ((2S,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl) carbamate(360 mg, 88%) as a white solid. LCMS m/z=329.3 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ 6.53 (br, 1H), 5.47 (d, J=6.8 Hz, 1H), 4.20-4.13 (m, 1H),3.99-3.90 (m, 1H), 3.41-3.21 (m, 2H), 2.83 (d, J=4.9 Hz, 3H), 1.75-1.61(m, 6H), 1.45 (s, 9H), 1.29-1.04 (m, 6H), 0.96-0.83 (m, 2H)

Step 3: (2S,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide

To a solution of tert-butyl ((2S,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl) carbamate(350 mg, 1.06 mmol) in DCM (2 mL) was added TFA (1 mL). The resultingmixture was stirred for 2 h. The solvent was removed to afford(2S,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide (370 mg,quant.). LCMS m/z=229.2 [M+H]⁺.

Synthesis of (2R,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide

Step 1: N-(tert-butoxycarbonyl)-O-(cyclohexylmethyl)-D-allothreonine

To a solution of O-benzyl-N-(tert-butoxycarbonyl)-D-allothreonine (70mg, 0.22 mmol) in IPA (2 mL) was added Rh—Al₂O₃(5%, 20 mg). Theresulting mixture was stirred overnight under an atmosphere of H₂. Thereaction mixture was filtered through celite and the solvent removed toafford N-(tert-butoxycarbonyl)-O-(cyclohexylmethyl)-D-allothreonine (50mg, 71%) as a colorless oil. LCMS m/z=316.1 [M+H]⁺.

Step 2: tert-butyl((2R,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate

To a solution ofN-(tert-butoxycarbonyl)-O-(cyclohexylmethyl)-D-allothreonine (50 mg,0.16 mmol) in DMF (1 mL) was added methylamine hydrochloride (13 mg,0.19 mmol), EDCI (46 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol) and DIPEA(62 mg, 0.48 mmol). The resulting mixture was stirred overnight. Waterwas added and the aqueous extracted with EtOAc. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. The solventwas removed and the residue purified by column chromatography (2%MeOH/DCM) to afford tert-butyl((2R,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate(38 mg, 73%) as a white solid. LCMS m/z=329.3 [M+H]⁺.

Step 3: (2R,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide

To a solution of tert-butyl((2R,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)carbamate(38 mg, 0.12 mmol) in a mixture of DCM (1 mL) and MeOH (1 mL) was addedTFA (1 mL). The resulting mixture was stirred for 2 h. The solvent wasremoved under reduced pressure to afford(2R,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide (27 mg, quant.)as a yellow oil. LCMS m/z=229.2 [M+H]⁺.

Synthesis of (2S,3S)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide

To a solution of (2S,3S)-2-amino-3-(benzyloxy)-N-methylbutanamide (100mg, 0.45 mmol) in AcOH (2 mL) was added PtO₂ (20 mg) and the mixture wasstirred under an atmosphere of H₂ (2 atm) overnight. The mixture wasfiltered through a pad of celite and the filtrate concentrated to afford(2 S,3 S)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide (90 mg, 87%).LCMS m/z=229.2 [M+H]⁺.

Synthesis of (S)-2-amino-5-(4-hydroxyphenyl)-N-methylpentanamide

Step 1: 1-(benzyloxy)-4-bromobenzene

To a solution of 4-bromophenol (1 g, 5.78 mmol) in DMF (20 mL) was addedBnBr (1.037 g, 6.07 mmol) and K₂CO₃ (2.4 g, 17.3 mmol). The resultingmixture was stirred at room temperature for 4 h. Water was added and theaqueous extracted with EtOAc three times. The combined organic layerswere washed with water, brine and dried over Na₂SO₄. The solvent wasremoved and the residue purified by column chromatography (5% MeOH/DCM)to afford 1-(benzyloxy)-4-bromobenzene (1.215 g, 80%) as a white solid.1H NMR (400 MHz, CD₃OD) δ 7.44-7.27 (m, 7H), 6.94-6.88 (m, 2H), 5.04 (s,2H).

Step 2: tert-butyl(S,E)-(5-(4-(benzyloxy)phenyl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate

To a solution of 1-(benzyloxy)-4-bromobenzene (100 mg, 0.38 mmol) in NMP(2 mL) was added tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (86.6 mg, 0.38 mmol),Pd(PPh₃)₄ (22 mg, 0.019 mmol) and NaOAc (62.3 mg, 0.76 mmol). Themixture was heated at 110° C. overnight. Water was added and the aqueousextracted with EtOAc three times. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. The solvent was removedand the residue purified by column chromatography (50% EtOAc/PE) toafford tert-butyl(S,E)-(5-(4-(benzyloxy)phenyl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(37.8 mg, 24.3%) as a white solid. LCMS m/z=411.2 [M+H]⁺.

Step 3: tert-butyl(S)-(5-(4-hydroxyphenyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(5-(4-(benzyloxy)phenyl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(37.8 mg, 0.092 mmol) in MeOH (1 mL) was added Pd/C (10%, 50 mg). Theresulting mixture was stirred for 3 h under an atmosphere of H₂. Thereaction mixture was filtered through celite and the solvent was removedto afford tert-butyl(S)-(5-(4-hydroxyphenyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate (33mg, quant) as a colorless oil. LCMS m/z=323.2 [M+H]⁺.

Step 4: (S)-2-amino-5-(4-hydroxyphenyl)-N-methylpentanamide

To a solution of tert-butyl(S)-(5-(4-hydroxyphenyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate (33mg, 0.102 mmol) in DCM (1 mL) was added HCl (4M in dioxane, 0.5 mL). Themixture was stirred at room temperature for 2 h. The solvent was removedto afford (S)-2-amino-5-(4-hydroxyphenyl)-N-methylpentanamide (25.5 g,quant.). LCMS m/z=223.1 [M+H]⁺.

Synthesis of (S)-2-amino-5-(4-hydroxycyclohexyl)-N-methylpentanamide

Step 1: tert-butyl(S)-(5-(4-hydroxycyclohexyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate

To a solution of tert-butyl(S)-(5-(4-hydroxycyclohexyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(200 mg, 0.048 mmol) in IPA (1 mL) was added Rh/Al₂O₃(5%, 49 mg). Themixture was stirred at room temperature under H₂ for 2 h. The reactionmixture was filtered through celite and the filterate concentrated toafford tert-butyl(S)-(5-(4-hydroxycyclohexyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(16.7 mg, quant.) as a colorless oil LCMS m/z=329.2 [M+H]⁺.

Step 2: (S)-2-amino-5-(4-hydroxycyclohexyl)-N-methylpentanamide

To a solution of tert-butyl(S)-(5-(4-hydroxycyclohexyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(16 mg, 0.048 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture wasstirred at room temperature for 1 h. The solvent was removed to afford(S)-2-amino-5-(4-hydroxycyclohexyl)-N-methylpentanamide (16 mg, quant).LCMS m/z=226.9 [M−H]⁻.

Synthesis of 2-(5-chloro-1H-benzo[d]imidazol-1-yl)acetic acid

Step 1: tert-butyl (4-chloro-2-nitrophenyl)glycinate

To a solution of 4-chloro-1-fluoro-2-nitrobenzene (200 mg, 1.14 mmol) inDMSO (3 mL) was added tert-butyl glycinate (164 mg, 1.25 mmol) and DIPEA(294 mg, 2.28 mmol). The resulting mixture was stirred and heated to 60°C. overnight. Water was added into the reaction mixture and the aqueousextracted with EtOAc. The combined organic layers were washed withwater, brine and dried over Na₂SO₄. The residue, after concentration waspurified by column chromatography (10% EtOAc/PE) to afford tert-butyl(4-chloro-2-nitrophenyl)glycinate (1.1 g, 73%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.42 (t, J=5.6 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H),6.99 (d, J=2.1 Hz, 1H), 6.76 (dd, J=9.1, 2.1 Hz, 1H), 4.19 (d, J=5.6 Hz,2H), 1.44 (s, 9H).

Step 2: tert-butyl (2-amino-4-chlorophenyl)glycinate

To a solution of tert-butyl (4-chloro-2-nitrophenyl)glycinate (100 mg,0.33 mmol) in MeOH (2 mL) was added Raney Ni (0.2 mL). The resultingmixture was stirred for 3 h under an atmosphere of H₂. The residue wasfiltered through celite, the solvent removed and the residue purified byprep-TLC (50% PE/EtOAc) to afford tert-butyl(2-amino-4-chlorophenyl)glycinate (40 mg, 42%) as a light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 6.52 (d, J=8.2 Hz, 1H), 6.43 (dd, J=8.2, 2.3Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 5.21 (t, J=6.3 Hz, 1H), 4.66 (s, 2H),3.79 (d, J=6.2 Hz, 2H), 1.42 (s, 9H).

Step 3: tert-butyl 2-(5-chloro-1H-benzo[d]imidazol-1-yl)acetate

To a solution of tert-butyl (2-amino-4-chlorophenyl)glycinate (20 mg,0.078 mmol) in MeOH (1 mL) was added trimethoxymethane (10 mg, 0.093mmol) and sulfamic acid (1 mg, 0.008 mmol). The resulting mixture wasstirred overnight. The solvent was removed under reduced pressure andthe residue was purified by prep-TLC (50% PE/EtOAc) to afford tert-butyl2-(5-chloro-1H-benzo[d]imidazol-1-yl)acetate (7 mg, 33%) as a lightyellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=1.4 Hz, 1H), 7.67 (d,J=8.7 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.29 (dd, J=8.6, 2.0 Hz, 1H),5.07 (s, 2H), 1.47 (s, 9H).

Step 4: 2-(5-chloro-1H-benzo[d]imidazol-1-yl)acetic acid

To a solution of tert-butyl 2-(5-chloro-1H-benzo[d]imidazol-1-yl)acetate(50 mg, 0.19 mmol) in DCM (2 mL) was added TFA (1.5 mL). The resultingmixture was stirred overnight. The solvent was removed under reducedpressure to afford 2-(5-chloro-1H-benzo[d]imidazol-1-yl)acetic acid as ayellow oil. LCMS m/z=210.9 [M+H]⁺.

Synthesis of 2-(6-cyano-1H-indol-3-yl)acetic acid

Step 1: ethyl 2-(6-cyano-1H-indol-3-yl)acetate

To a solution of 1H-indole-6-carbonitrile (200 mg, 1.41 mmol) in DCM (5mL) was added ethyl 2-diazoacetate (293 mg, 2.57 mmol) and Cu(OTf)₂ (62mg, 0.17 mmol). The resulting mixture was stirred at room temperatureovernight. The residue, after concentration, was purified by columnchromatography (10% EtOAc/PE) to afford ethyl2-(6-cyano-1H-indol-3-yl)acetate (40 mg, 12.4%) as a colorless oil.

Step 2: 2-(6-cyano-1H-indol-3-yl)acetic acid

To a solution of ethyl 2-(6-cyano-1H-indol-3-yl)acetate (40 mg, 0.18mmol) in THF/H₂O (1.5 mL/1.5 mL) was added LiOH.H₂O (22.1 mg, 0.53mmol). The resulting mixture was stirred at room temperature for 3 h.The aqueous was acidified to pH=2-3 by adding 1 M HCl and extracted withEtOAc three times. The combined organic phases were concentrated underreduced pressure to afford 2-(6-cyano-1H-indol-3-yl)acetic acid (28 mg,79.8%) as a white solid. LCMS m/z=199.0 [M−H]⁻.

Synthesis of 2-(6-chlorobenzofuran-3-yl)acetic acid

Step 1: ethyl 2-(6-chlorobenzofuran-3-yl)acetate

A mixture of 6-chlorobenzofuran-3(2H)-one (169 mg, 1.0 mmol) and ethyl(triphenylphosphoranylidene)acetate (524 mg, 1.5 mmol) in toluene (10mL) was heated at reflux for 24 h. The reaction mixture was concentratedin vacuo and the residue purified by column chromatography (10%EtOAc/PE) to give ethyl 2-(6-chlorobenzofuran-3-yl)acetate (171 mg,72%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, J=1.1 Hz, 1H), 7.74 (d, J=1.8Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 1.9 Hz, 1H), 4.11 (q,J=7.1 Hz, 2H), 3.79 (d, J=1.1 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H).

Step 2: 2-(6-chlorobenzofuran-3-yl)acetic acid

A mixture of ethyl 2-(6-chlorobenzofuran-3-yl)acetate (155 mg, 0.65mmol) and KOH (55 mg, 0.98 mmol) in EtOH (5 mL) was heated at 80° C. for1 h. The reaction mixture was acidified by adding of 1M HCl andextracted with EtOAc three times. The combined organic layers werewashed with water and brine, dried over Na₂SO₄ and concentrated in vacuoto give 2-(6-chlorobenzofuran-3-yl)acetic acid (132 mg, 96% yield).

Synthesis of (S)-2-amino-N-methyl-5-(pyridin-2-yl)pentanamide

Step 1: tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(pyridin-3-yl)pent-4-en-2-yl)carbamate

A mixture of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (50 mg, 0.22 mmol),3-bromopyridine (31 mg, 0.20 mmol), Pd(OAc)₂ (5 mg), NaHCO₃ (55 mg, 0.66mmol) in DMF/H₂O (1 mL/0.2 mL) wad heated at 70° C. for 4 h under anatmosphere of N2. Water was added and the aqueous extracted with EtOAc.The combined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed and the residue purified by prep-TLC (8%MeOH/DCM) to afford tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(pyridin-3-yl)pent-4-en-2-yl)carbamate(24 mg, 35%) as a yellow oil. LCMS m/z=306.1[M+H]⁺.

Step 2: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-3-yl)pentan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(pyridin-3-yl)pent-4-en-2-yl)carbamate(80 mg, 0.26 mmol) in MeOH (10 mL) was added Pd/C (10%, 8 mg). Theresulting mixture was stirred for 14 h under an atmosphere of H₂. Thereaction mixture was filtered through celite and the filtrate wasconcentrated to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-3-yl)pentan-2-yl)carbamate (80.5mg, quant.) as a yellow oil. LCMS m/z=308.2 [M+H]⁺.

Step 3: (S)-2-amino-N-methyl-5-(pyridin-2-yl)pentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-3-yl)pentan-2-yl)carbamate (74 mg,0.23 mmol) in DCM (3.0 mL) was added TFA (0.5 mL). The resulting mixturewas stirred for 3 h. The solvent was removed under reduced pressure toafford (S)-2-amino-N-methyl-5-(pyridin-2-yl)pentanamide (51 mg, quant.).

Synthesis of 5-benzylpyridin-3-amine

Step 1: 3-benzyl-5-nitropyridine

To a solution of 3-bromo-5-nitropyridine (200 mg, 0.985 mmol) in amixture of dioxane (15 mL) and water (3 mL) was added2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (322.3 mg, 1.48 mmol),Pd(dppf)₂Cl₂ (144.2 mg, 0.197 mmol) and K₃PO₄ (627.4 mg, 2.96 mmol). Theresulting mixture was heated at 90° C. for 5 h. Water was added into thereaction mixture and the aqueous extracted with EtOAc three times. Thecombined organic layers were washed with water, brine and dried overNa₂SO₄. The residue, after concentration was purified by columnchromatography (25% EtOAc/PE) to afford 3-benzyl-5-nitropyridine (92 mg,44%). LCMS m/z=215.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.20 (d, J=2.4Hz, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.39 (t, J=2.2 Hz, 1H), 7.38-7.21 (m,5H), 4.16 (s, 2H).

Step 2: 5-benzylpyridin-3-amine

To a solution of 3-benzyl-5-nitropyridine (92 mg, 0.43 mmol) in MeOH (3mL) was added Pd/C (10.0 mg). The reaction mixture was stirred under H₂for 5 h. After filtration through a pad of celite, the filtrate wasconcentrated to afford 5-benzylpyridin-3-amine (60 mg, 75%) as a whitesolid. LCMS m/z=185.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.75 (d, J=2.6Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.35-7.25 (m, 2H), 7.20 (d, J=7.5 Hz,3H), 6.68 (s, 1H), 5.21 (s, 2H), 3.79 (s, 2H).

Synthesis of 2-benzylpyridin-4-amine

Made using a similar method as described for the synthesis of5-benzylpyridin-3-amine, using 2-bromo-4-nitropyridine in place of3-bromo-5-nitropyridine

Synthesis of 5-phenoxypyridin-3-amine

Step 1: 3-nitro-5-phenoxypyridine

A mixture of 3-bromo-5-nitropyridine (500 mg, 2.46 mmol), phenol (255mg, 2.71 mmol) and K₃CO₃ (408 mg, 2.96 mmol) in DMSO (6 mL) was stirredat 120° C. for 3 h. Water was added into the reaction mixture and theaqueous extracted with EtOAc three times. The combined organic layerswere washed with water, brine, dried over Na₂SO₄. The residue, afterconcentration was purified by column chromatography (10% EtOAc/PE) toafford 3-nitro-5-phenoxypyridine (93 mg, 17%) as a white solid. LCMSm/z=217.0 [M+H]⁺.

Step 2: 5-phenoxypyridin-3-amine

To a solution of 3-nitro-5-phenoxypyridine (93 mg, 0.43 mmol) in MeOH (1mL) was added 10% Pd/C (10 mg). The resulting mixture was stirred underH₂ for 3 h. After filtration through a pad of celite, the filtrate wasconcentrated to afford 5-phenoxypyridin-3-amine (50 mg, 62%) as a whitesolid. LCMS m/z=187.1 [M+H]⁺.

Synthesis of (2S,3S)-2-amino-3-((4-fluorobenzyl)oxy)butanamide

Step 1: N-(tert-butoxycarbonyl)-O-(4-fluorobenzyl)-L-allothreonine

To a solution of (tert-butoxycarbonyl)-L-allothreonine (500 mg, 2.28mmol) in DMF (5.0 mL) was added NaH (187 mg, 4.67 mmol) portionwise at0° C. After stirring for 1 h, 1-(bromomethyl)-4-fluorobenzene (431 mg,2.28 mmol) was added and the reaction mixture was stirred for another 14h. The residue, after concentration was purified by reverse-phase columnto afford N-(tert-butoxycarbonyl)-O-(4-fluorobenzyl)-L-allothreonine(140 mg, 19%) as off-white solid. LCMS m/z=328.2 [M+H]⁺.

Step 2: tert-butyl((2S,3S)-1-amino-3-(4-fluorobenzyl)oxy)-1-oxobutan-2-yl)carbamate

HATU (179 mg, 0.47 mmol) was added to the solution ofN-(tert-butoxycarbonyl)-O-(4-fluorobenzyl)-L-allothreonine (100 mg, 0.92mmol) in DMF (2.0 mL) at 0° C. After stirring for 30 min, NH₄Cl (50 mg,0.93 mmol) was added and the solution was stirred for another 2 h. Theresidue, after concentration was purified by reverse-phase column toafford tert-butyl((2S,3S)-1-amino-3-((4-fluorobenzyl)oxy)-1-oxobutan-2-yl)carbamate (50mg, 50%) as a colorless oil. LCMS m/z=327.1 [M+1]⁺; ¹H NMR (400 MHz,CD₃OD) δ 7.40-7.33 (m, 2H), 7.07-7.00 (m, 2H), 4.53 (s, 2H), 4.33 (d,J=6.0 Hz, 1H), 3.85 (t, J=6.4 Hz, 1H), 1.45 (s, 9H), 1.19 (d, J=6.3 Hz,3H).

Step 3: (2S,3S)-2-amino-3-(4-fluorobenzyl)oxy)butanamide

TFA (2.0 mL) was added to the solution of tert-butyl ((2S,3S)-1-amino-3-((4-fluorobenzyl)oxy)-1-oxobutan-2-yl)carbamate (50 mg,0.15 mmol) in DCM (2.0 mL) and the reaction mixture was stirred for 3 h.The solvent was removed under reduced pressure to afford(2S,3S)-2-amino-3-((4-fluorobenzyl)oxy)butanamide (209 mg, quant.) as ayellow oil. LCMS m/z=226.9 [M+H]⁺.

Synthesis of (2S,3R)-2-amino-3-((4-fluorobenzyl)oxy)butanamide

Made using a similar method as described for the synthesis of(2S,3S)-2-amino-3-((4-fluorobenzyl)oxy)butanamide, starting from(tert-butoxycarbonyl)-L-threonine. LCMS m/z=227.0 [M+H]⁺.

Synthesis of 4-(2-cyclopropylacetamido)-3-methoxybenzoic acid

Step 1: Methyl 4-(2-cyclopropylacetamido)-3-methoxybenzoate

2-cyclopropylacetic acid (332 mg, 3.31 mmol) was added to the solutionof methyl 4-amino-3-methoxybenzoate (500 mg, 2.76 mmol), DIEA (1.07 g,8.28 mmol) and HATU (380.23 mg, 4.14 mmol) in DMA (15.0 mL). Thesolution was stirred at room temperature for 14 h. The reaction wastreated with water and extracted with EtOAc three times. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography (2%MeOH/DCM) to give methyl 4-(2-cyclopropylacetamido)-3-methoxybenzoate(333 mg, 46%) as a white solid. LCMS m/z=264.1 [M+H]⁺.

Step 2: 4-(2-cyclopropylacetamido)-3-methoxybenzoic acid

To a solution of methyl 4-(2-cyclopropylacetamido)-3-methoxybenzoate (50mg, 0.19 mmol) in MeOH/H₂O (1 mL/0.2 mL) was added NaOH (22.8 mg, 0.57mmol). The resulting mixture was stirred for 4 h. The reaction wastreated with water and pH of the aqueous was adjusted to ˜1 by adding of1M HCl then extracted with EtOAc. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. Concentration afforded4-(2-cyclopropylacetamido)-3-methoxybenzoic acid (40 mg, 85%) as ayellow solid. LCMS m/z=250.1 [M+H]⁺.

Synthesis of (S)-2-amino-5-(2-hydroxyphenyl)-N-methylpentanamide

Step 1: 1-(benzyloxy)-2-bromobenzene ( )

BnBr (2.17 g, 12.7 mmol) was added to the solution of 3-bromophenol (2g, 11.6 mmol) and K₂CO₃ (3.2 g, 23.2 mmol) in DMF (10.0 mL). Thesolution was stirred at room temperature for 3 h. The reaction wastreated with water and extracted with EtOAc three times. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography (20%EtOAc/PE) to afford 1-(benzyloxy)-2-bromobenzene (2.8 g, 92%) as ayellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.58-7.20 (m, 7H), 7.00-6.82 (m,2H), 5.04 (s, 2H).

Step 2: tert-butyl(S,Z)-(5-(2-(benzyloxy)phenyl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate

To a solution of 1-(benzyloxy)-2-bromobenzene (1 g, 3.80 mmol) in NMP(10.0 mL) was added tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (1.04 g, 4.56 mmol),Pd(PPh₃)₄ (218 mg, 1.90 mmol) and NaOAc (1.55 g, 11.4 mmol). Theresulting mixture was heated at 100° C. for 14 h. The reaction wastreated with water and extracted with EtOAc. The combined organic layerswere washed with water and brine, dried over Na₂SO₄ and concentrated.The residue was purified by column chromatography (20% EtOAc/PE) toafford tert-butyl(S,Z)-(5-(2-(benzyloxy)phenyl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(300 mg, 40%) as a yellow oil. LCMS m/z=411.1 [M+H]⁺.

Step 3: tert-butyl(S)-(5-(2-hydroxyphenyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate

Pd/C (5 mg) was added to the solution of tert-butyl(S,Z)-(5-(2-(benzyloxy)phenyl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(50 mg, 0.12 mmol) in MeOH (1.5 mL) and the reaction was stirred at roomtemperature for 14 h under an atmosphere of H₂. The mixture was filteredthrough a pad of celite and the filtrate was concentrated to affordtert-butyl(S)-(5-(2-hydroxyphenyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate (35mg, quant.) which was used in next step without further purification.LCMS m/z=323.3 [M+H]⁺.

Step 4: (S)-2-amino-5-(2-hydroxyphenyl)-N-methylpentanamide

TFA (1.5 mL) was added to a solution of tert-butyl(S)-(5-(2-hydroxyphenyl)-1-(methylamino)-1-oxopentan-2-yl)carbamate (40mg, 0.12 mmol) in DCM (2.0 mL) and the reaction was stirred for 4 h. Thesolvent was removed to afford(S)-2-amino-5-(2-hydroxyphenyl)-N-methylpentanamide (30 mg, quant.)which was used without further purification.

Synthesis of (S)-2-amino-5-(3-hydroxyphenyl)-N-methylpentanamide

Made using a similar method as described for the synthesis of(S)-2-amino-5-(2-hydroxyphenyl)-N-methylpentanamide. LCMS m/z=223.1[M+H]⁺.

Synthesis of 2-(6-chloro-1H-indol-3-yl)propanoic acid

Step 1: methyl 2-(6-chloro-1H-indol-3-yl)acetate

To a solution of 2-(6-chloro-1H-indol-3-yl)acetic acid (500 mg, 2.392mmol) in MeOH (5 mL) was added conc. H₂SO₄ (1 mL). The resulting mixturewas heated at 80° C. for 2 h then the solvent removed under vacuum. Theresidue obtained was diluted with water and and the pH adjusted to ˜8 byaddition of 10% NaOH. The aqueous layer was extracted with EtOAc threetimes and the combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated to afford methyl2-(6-chloro-1H-indol-3-yl)acetate (490 mg, 92%) as a white solid. LCMSm/z=223.9 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.46 (d, J=8.4 Hz, 1H), 7.34(d, J=1.9 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 6.99 (dd, J=8.4, 1.9 Hz, 1H),3.75 (d, J=0.8 Hz, 2H), 3.67 (s, 3H).

Step 2: ethyl 6-chloro-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate

To a solution of methyl 2-(6-chloro-1H-indol-3-yl)acetate (350 mg, 1.569mmol) in DCM (3 ml) was added ethyl carbonochloridate (340 mg, 3.139mmol) and TBAI (57 mg, 0.157 mmol). The resulting mixture was stirred at0° C. for 2 h. The mixture was diluted with water and extracted withEtOAc three times. The combined organic layers were washed with waterand brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (20% EtOAc/PE) to afford ethyl6-chloro-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (440 mg, 95%)as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (d, J=1.9 Hz, 1H), 7.61(t, J=1.1 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.23 (dd, J=8.4, 1.9 Hz, 1H),4.48 (q, J=7.1 Hz, 2H), 3.74 (d, J=1.0 Hz, 2H), 3.70 (s, 3H), 1.45 (t,J=7.1 Hz, 3H).

Step 3: ethyl6-chloro-3-(1-methoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate

To a solution of ethyl6-chloro-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (440 mg, 1.49mmol) in dry THF (3 mL) was added LDA (2M in THF, 1.2 mL, 2.4 mmol) andMeI (318 mg, 2.24 mmol) under N₂ atmosphere at −70° C. The mixture wasallowed to warm to room temperature and stirred for another 5 h. Waterwas added and the aqueous extracted with EtOAc three times. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Theresidue obtained after concentration was purified by columnchromatography (10% EtOAc/PE) to afford ethyl6-chloro-3-(1-methoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (70 mg,15%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.57 (dd,J=2.5, 1.3 Hz, 1H), 7.45 (dt, J=8.5, 1.9 Hz, 1H), 7.20 (dq, J=8.5, 1.6Hz, 1H), 4.46 (qd, J=7.1, 1.0 Hz, 2H), 3.70 (d, J=7.3 Hz, 6H), 1.44 (t,J=7.1 Hz, 4H).

Step 4: 2-(6-chloro-1H-indol-3-yl)propanoic acid

To a solution of ethyl6-chloro-3-(1-methoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (70 mg,0.226 mmol) in DMF (1 mL) was added 10% NaOH (1 ml). The resultingmixture was stirred for 3 h then the solvent removed under vacuum. Theresidue obtained was diluted with water and and the pH adjusted to ˜2 byaddition of 1M HCl. The aqueous layer was extracted with EtOAc threetimes and the combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated to afford2-(6-chloro-1H-indol-3-yl)propanoic acid (45 mg, 90%) as a white solid.LCMS m/z=221.9 [M−H]⁻.

Synthesis of(S)-2-amino-N-methyl-5-(tetrahydro-2H-pyran-4-yl)pentanamide

Step 1: 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

To a solution of tetrahydro-4H-pyran-4-one (500 mg, 4.995 mmol) in dryTHF (3 mL) was added LiHMDS (1M in THF, 6 mL, 5.994 mmol) and phenyltriflimide (1.96 g, 5.494 mmol) at ˜78° C. The resulting mixture wasstirred at room temperature overnight. Water was added and the aqueousextracted with EtOAc three times. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. The residue, afterconcentration was purified by column chromatography (6% EtOAc/PE) toafford 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (350 mg, 30%)as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 5.92 (tt, J=2.9, 1.4 Hz, 1H),4.24 (q, J=2.9 Hz, 2H), 3.87 (t, J=5.5 Hz, 2H), 2.46 (ttd, J=5.5, 2.8,1.4 Hz, 2H).

Step 2: tert-butyl(S,E)-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate

To a solution of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate(300 mg, 1.293 mmol) in a mixture of DMF (4 mL) and H₂O (1 mL) was addedtert-butyl (S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (265 mg,1.164 mmol), NaHCO₃ (326 mg, 3.879 mmol) and Pd(OAc)₂ (29 mg, 0.129mmol). The resulting mixture was heated at 100° C. overnight under N₂atmosphere. Water was added and the aqueous extracted with EtOAc threetimes. The combined organic layers were washed with water, brine anddried over Na₂SO₄. The residue after concentration was purified bycolumn chromatography (20% EtOAc/PE) to afford tert-butyl(S,E)-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(180 mg, 45%) as a yellow oil. LCMS m/z=311.2 [M+H]⁺.

Step 3: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(tetrahydro-2H-pyran-4-yl)pentan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(45 mg, 0.145 mmol) in MeOH (1 mL) was added 10% Pd/C (10 mg). Theresulting mixture was stirred at room temperature for 3 h under H₂atmosphere. The mixture was filtered through celite and the filtrate wasconcentrated to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(tetrahydro-2H-pyran-4-yl)pentan-2-yl)carbamate(40 mg, 88%) as a white oil. LCMS m/z=315.2 [M+H]⁺.

Step 4: (S)-2-amino-N-methyl-5-(tetrahydro-2H-pyran-4-yl)pentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(tetrahydro-2H-pyran-4-yl)pentan-2-yl)carbamate(40 mg, 0.127 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 1 mL).The mixture was stirred at room temperature for 3 h. The solvent wasremoved under reduced pressure to afford(S)-2-amino-N-methyl-5-(tetrahydro-2H-pyran-4-yl)pentanamide which wasused directly in next step. LCMS m/z=215.1 [M+H]⁺.

Synthesis of 2-(5,6-dichloro-1H-indol-3-yl)acetic acid

Step 1: ethyl 2-(5,6-dichloro-1H-indol-3-yl)acetate

To a solution of 5,6-dichloro-1H-indole (2.0 g, 10.82 mmol) in DCM (10mL) was added ethyl 2-diazoacetate (1.8 g, 16.2 mmol) and Cu(OTf)₂ (180mg, 1.1 mmol). The resulting mixture was stirred at room temperatureovernight. Water was added and the aqueous extracted with DCM threetimes. The combined organic layers were washed with water, brine, driedover Na₂SO₄. The residue after concentration was purified by columnchromatography (20% EtOAc/PE) to afford ethyl2-(5,6-dichloro-1H-indol-3-yl)acetate (700 mg, 24%) as a yellow oil.LCMS m/z=269.8 [M−H]⁻.

Step 2: 2-(5,6-dichloro-1H-indol-3-yl)acetic acid

To a solution of ethyl 2-(5,6-dichloro-1H-indol-3-yl)acetate (100 mg,0.37 mmol) in THF (1 mL) was added 10% NaOH (1 mL). The resultingmixture was stirred for 3 h then the solvent removed under vacuum. Theresidue obtained was diluted with water and the pH adjusted to ˜2 byaddition of 1M HCl. The aqueous layer was extracted with EtOAc threetimes and the combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated to afford2-(5,6-dichloro-1H-indol-3-yl)acetic acid (70 mg, 78%) as a white solid.LCMS m/z=241.8 [M−H]⁻. ¹H NMR (400 MHz, CD₃OD) δ 7.68 (d, J=9.1 Hz, 1H),7.49 (d, J=2.1 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 3.70 (d, J=0.9 Hz, 2H).

Synthesis of 2-(7-methoxy-1H-indol-3-yl)acetic acid

Made using a similar method as described for the synthesis of2-(5,6-dichloro-1H-indol-3-yl)acetic acid, starting from7-methoxy-1H-indole. LCMS m/z=206.0 [M+H]⁺.

Synthesis of(S)-2-amino-N-methyl-5-(4-(trifluoromethyl)phenyl)pentanamide

Step 1: tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)phenyl)pent-4-en-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (100 mg, 0.446 mmol)in NMP (3 mL) was added 1-bromo-4-(trifluoromethyl)benzene (100 mg,0.446 mmol), Pd(PPh₃)₄ (25 mg, 0.023 mmol) and NaOAc (73 mg, 0.892mmol). The resulting mixture was heated at 100° C. for 4 h. Water wasadded and the aqueous extracted with EtOAc three times. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Theresidue after concentration was purified by column chromatography (20%EtOAc/PE) to afford tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)phenyl)pent-4-en-2-yl)carbamate(140 mg, 84%) as a white oil. LCMS m/z=373.0 [M+H]⁺.

Step 2: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)phenyl)pentan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)phenyl)pent-4-en-2-yl)carbamate(100 mg, 0.27 mmol) in MeOH (1 mL) was added 10% Pd/C (14 mg). Theresulting mixture was stirred at room temperature for 6 h under H₂atmosphere. The mixture was filtered through a pad of celite and thefiltrate was concentrated to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)phenyl)pentan-2-yl)carbamate(70 mg, 71%) as a colorless oil. LCMS m/z=375.1 [M+H]⁺.

Step 3: (S)-2-amino-N-methyl-5-(4-(trifluoromethyl)phenyl)pentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(4-(trifluoromethyl)phenyl)pentan-2-yl)carbamate(50 mg, 0.167 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 1 mL).The mixture was stirred at room temperature for 3 h. The solvent wasremoved under reduced pressure and the product was used directly. LCMSm/z=275.0 [M+H]⁺.

Synthesis of (S,E)-2-amino-N-methyl-5-phenylpent-4-enamide

Step 1: tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-phenylpent-4-en-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (450 mg, 1.973 mmol)in NMP (3 mL) was added bromobenzene (300 mg, 1.923 mmol), Pd(PPh₃)₄(114 mg, 0.099 mmol) and NaOAc (324 mg, 3.946 mmol). The resultingmixture was heated at 100° C. for 4 h. Water was added and the aqueousextracted with EtOAc three times. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. The residue afterconcentration was purified by column chromatography (20% EtOAc/PE) toafford tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-phenylpent-4-en-2-yl)carbamate (140 mg,84%) as a white solid. LCMS m/z=305.0 [M+H]⁺.

Step 2: (S,E)-2-amino-N-methyl-5-phenylpent-4-enamide

To a solution of tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-phenylpent-4-en-2-yl)carbamate (50 mg,0.167 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 1 mL). Themixture was stirred at room temperature for 3 h. The solvent was removedunder reduced pressure to afford(S,E)-2-amino-N-methyl-5-phenylpent-4-enamide which was used directly.LCMS m/z=205.0 [M+H]⁺.

Synthesis of (S)-2-amino-N-methyl-5-phenylpent-4-ynamide

Step 1: tert-butyl(S)-(1-(methylamino)-1-oxo-5-phenylpent-4-yn-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (100 mg, 0.442 mmol)in NMP (3 mL) was added iodobenzene (300 mg, 1.923 mmol), PdCl₂(PPh₃)₂(30 mg, 0.044 mmol) and CuI (8 mg, 0.044 mmol). The resulting mixturewas heated at 100° C. for 4 h under N₂ atmosphere. Water was added andthe aqueous extracted with EtOAc three times. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. The residueafter concentration was purified by column chromatography (20% EtOAc/PE)to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-phenylpent-4-yn-2-yl)carbamate (82 mg, 62%)as a white solid. LCMS m/z=303.2 [M+H]⁺.

Step 2: (S)-2-amino-N-methyl-5-phenylpent-4-ynamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-phenylpent-4-yn-2-yl)carbamate (50 mg,0.167 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 1 mL). Themixture was stirred at room temperature for 3 h. The solvent was removedunder reduced pressure to afford(S)-2-amino-N-methyl-5-phenylpent-4-ynamide which was used directly innext step. LCMS m/z=203.2 [M+H]⁺.

Synthesis of (S)-2-amino-N-methyl-5-(pyridin-4-yl)pentanamide

Step 1: tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(pyridin-4-yl)pent-4-en-2-yl)carbamate

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (200 mg, 0.877 mmol)in a mixture of DMF (4 mL) and H₂O (2 mL) was added 4-bromopyridine (187mg, 0.964 mmol), Pd(OAc)₂ (20 mg) and NaHCO₃ (294 mg, 3.5 mmol). Theresulting mixture was heated at 70° C. overnight. Water was added andthe aqueous extracted with EtOAc three times. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. Residueafter concentration was purified by prep-HPLC to afford tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(pyridin-4-yl)pent-4-en-2-yl)carbamate(70 mg, 26%) as a white solid. LCMS m/z=306.0 [M+H]⁺.

Step 2: tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-4-yl)pentan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(1-(methylamino)-1-oxo-5-(pyridin-4-yl)pent-4-en-2-yl)carbamate(70 mg, 0.23 mmol) in THF (2 mL) was added Pd/C (10%, 50 mg). Themixture was stirred at room temperature for 2 h under an atmosphere ofH₂. The reaction mixture was filtered through celite and the filtratewas concentrated to afford tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-4-yl)pentan-2-yl)carbamate (70 mg,quant.) as a colorless oil. LCMS m/z=308.0 [M+H]⁺.

Step 3: (S)-2-amino-N-methyl-5-(pyridin-4-yl)pentanamide

To a solution of tert-butyl(S)-(1-(methylamino)-1-oxo-5-(pyridin-4-yl)pentan-2-yl)carbamate (70 mg,0.228 mmol) in MeOH (1 mL) was added HCl (4M in dioxane, 2 mL). Theresulting mixture was stirred at room temperature for 1 h. The solventwas removed to afford (S)-2-amino-N-methyl-5-(pyridin-4-yl)pentanamide(50 mg, quant.) LCMS m/z=208.0 [M+H]⁺.

Synthesis of 6-benzylpyridin-3-amine

Step 1: 2-benzyl-5-nitropyridine

A mixture of 2-bromo-5-nitropyridine (500 mg, 2.46 mmol),2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (218 mg, 3.69 mmol)Pd(dppf)Cl₂ (cat.) and K₃PO₄ (1.57 g, 7.39 mmol) in a mixture of dioxane(5 mL) and H₂O (1 mL) was heated at 90° C. for 2 h. Water was added andthe aqueous extracted with EtOAc three times. The combined organiclayers were washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography (10%EtOAc/PE) to afford 2-benzyl-5-nitropyridine (249 mg, 47%) as a whitesolid. LCMS m/z=215.2 [M+H]⁺.

Step 2: 6-benzylpyridin-3-amine

To a solution of 2-benzyl-5-nitropyridine (249 mg, 1.16 mmol) in MeOH (3mL) was added 10% Pd/C (10 mg). The resulting mixture was stirred for 3h under an atmosphere of H₂. The mixture was filtered through celite andthe filtrate was concentrated to afford 6-benzylpyridin-3-amine (100 mg,47% yield) as a white solid. LCMS m/z=185.1 [M+H]⁺.

Synthesis of(S)-2-amino-5-(1H-benzo[d][1,2,3]triazol-4-yl)-N-methylpentanamide

Step 1: 4-bromo-1H-benzo[d][1,2,3]triazole

TBN (2.2 g, 21.4 mmol) was added to a solution of3-bromobenzene-1,2-diamine (2 g, 10.7 mmol) in DCM (15 mL). The solutionwas stirred at room temperature for 2 h. The solvent was removed and theresidue was purified by column chromatography (2% MeOH/DCM) to give4-bromo-1H-benzo[d][1,2,3]triazole (1.7 g, 81%) as a yellow oil. LCMSm/z=197.9 [M+H]⁺.

Step 2: 4-bromo-1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazole

To a solution of 4-bromo-1H-benzo[d][1,2,3]triazole (1.6 mg, 8.04 mmol)in DCM (10.0 mL) was added PMBCl (1.38 g, 8.84 mmol) and TEA (2.9 g,27.21 mmol). The resulting mixture was stirred for 4 h. The solvent wasremoved and the residue was purified by column chromatography (2%MeOH/DCM) to give 4-bromo-1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazole(1.1 g, 41%) as a yellow solid. LCMS m/z=317.8 [M+H]⁺.

Step 3: tert-butyl(S,E)-(5-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate

To a solution of 4-bromo-1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazole(950 mg, 2.99 mmol) in a mixture of DMF (10 mL) and H₂O (2 mL) was addedtert-butyl (S)-(1-(methylamino)-1-oxopent-4-en-2-yl)carbamate (820 mg,3.60 mmol), Pd(OAc)₂ (67 mg, 0.03 mmol) and NaHCO₃ (754 mg, 8.97 mmol).The resulting mixture was heated at 70° C. for 14 h. Water was added andthe aqueous extracted with EtOAc three times. The combined organiclayers were washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography (2%MeOH/DCM) to afford tert-butyl(S,E)-(5-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(600 mg, 43%) as a white solid. LCMS m/z=466.1 [M+H]⁺.

Step 4: tert-butyl(S)-(5-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopentan-2-yl)carbamate

Pd/C (10%, 84 mg) was added to a solution of tert-butyl(S,E)-(5-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopent-4-en-2-yl)carbamate(280 mg, 0.77 mmol) in MeOH (5 mL) and the reaction mixture was stirredunder H₂ atmosphere for 14 h. The mixture was filtered through a pad ofcelite and the filtrate was concentrated to afford tert-butyl(S)-(5-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(250 mg, quant.) which was used in next step without furtherpurification. LCMS m/z=468.1 [M+H]⁺.

Step 5: tert-butyl(S)-(5-(1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopentan-2-yl)carbamate

To a solution of tert-butyl(S)-(5-(1-(4-methoxybenzyl)-1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(180 mg, 0.48 mmol) in a mixture of DMF (5 mL) and H₂O (1 mL) was addedCAN (808 mg, 1.48 mmol). The resulting mixture was stirred at roomtemperature for 4 h. Water was added and the aqueous extracted withEtOAc three times. The combined organic layers were washed with waterand brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby prep-TLC to give tert-butyl(S)-(5-(1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(40 mg, 34%) as a yellow solid. LCMS m/z=348.0 [M+H]⁺.

Step 6:(S)-2-amino-5-(1H-benzo[d][1,2,3]triazol-4-yl)-N-methylpentanamide

TFA (0.5 mL) was added to a solution of tert-butyl(S)-(5-(1H-benzo[d][1,2,3]triazol-4-yl)-1-(methylamino)-1-oxopentan-2-yl)carbamate(40 mg, 0.11 mmol) in DCM (1.5 mL) and the reaction was stirred for 4 h.The solvent was removed to afford(S)-2-amino-5-(1H-benzo[d][1,2,3]triazol-4-yl)-N-methylpentanamide (32mg, quant.) which was used without further purification.

Synthesis of 2-(6-(cyclopropylmethoxy)-1H-indol-3-yl)acetic acid

Step 1: 6-(cyclopropylmethoxy)-1H-indole

To a solution of 1H-indol-6-ol (500 mg, 3.76 mmol) in acetone (10 mL)was added (bromom-ethyl)cyclopropane (0.8 mL) and K₂CO₃ (1.55 g, 11.3mmol). The mixture was heated at reflux for 24 h and an additionalamount of (bromomethyl)cyclopropane (0.5 mL) was added. The mixture washeated at reflux for additional 2 days. The reaction mixture wasconcentrated in vacuo. The crude was purified by column chromatography(15% EtOAc/PE) to give 6-(cyclopropylmethoxy)-1H-indole (570 mg, 81%).LCMS m/z=188.0 [M+H]⁺.

Step 2: ethyl 2-(6-(cyclopropylmethoxy)-1H-indol-3-yl)acetate

To a solution of 6-(cyclopropylmethoxy)-1H-indole (100 mg, 0.53 mmol)and Cu(OTf)₂ (19 mg, 0.05 mmol) in DCM (3 mL) was added ethyldiazoacetate (430 mg, 3.77 mmol) dropwise. The mixture was stirred atroom temperature for 24 h. The reaction mixture was concentrated invacuo and the residue was purified by column chromatography (12%EtOAc/PE) to give ethyl 2-(6-(cyclopropylmethoxy)-1H-indol-3-yl)acetate(122 mg, 14.6%). LCMS m/z=274.1 [M+H]⁺.

Step 3: 2-(6-(cyclopropylmethoxy)-1H-indol-3-yl)acetic acid

To a solution of ethyl 2-(6-(cyclopropylmethoxy)-1H-indol-3-yl)acetate(122 mg, 0.45 mmol) in MeOH (1 mL) was added 10% NaOH (4 mL). Themixture was stirred at room temperature for 3 h. The pH was adjusted to˜2 by addition of 1M HCl and the aqueous extracted with EtOAc threetimes. The combined organic layers were concentrated in vacuo to afford2-(6-(cyclopropylmethoxy)-1H-indol-3-yl)acetic acid which was useddirectly in the synthesis of further compounds.

Synthesis of 1-(oxazol-2-yl)-4-phenylbutan-1-amine

Step 1: (S)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfinamide

A mixture of oxazole-2-carbaldehyde (300 mg, 3.09 mmol),(S)-2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and Ti(OEt)₄ (1.41g, 6.18 mmol) in THF (10.0 mL) was stirred at room temperatureovernight. Water was added and the aqueous extracted with EtOAc threetimes. The organic layers were washed with water, brine, dried overNa₂SO₄ and concentrated in vacuo. The crude was purified by silicacolumn chromatography (30% EtOAc/PE) to give(S)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfinamide (300 mg,49%). LCMS m/z=201.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=1.0Hz, 1H), 7.84 (s, 1H), 7.41 (s, 1H), 1.29 (d, J=1.1 Hz, 9H).

Step 2:(S)-2-methyl-N-(1-(oxazol-2-yl)-4-phenylbutyl)propane-2-sulfinamide

To a solution of(S)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfinamide (300 mg, 1.5mmol) in dry THF was added (3-phenylpropyl)magnesium bromide (1.67 g,7.49 mmol) at ˜78° C. The mixture was stirred at room temperature underan atmosphere of N2. NH₄C1 solution was added and the aqueous extractedwith EtOAc three times. The combined organic layers were washed withwater, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude waspurified by prep-HPLC to give(S)-2-methyl-N-(1-(oxazol-2-yl)-4-phenylbutyl)propane-2-sulfinamide (82mg, 17%). LCMS m/z=321.2 [M+H]⁺.

Step 3: 1-(oxazol-2-yl)-4-phenylbutan-1-amine

A solution of(S)-2-methyl-N-(1-(oxazol-2-yl)-4-phenylbutyl)propane-2-sulfinamide (82mg, 0.256 mmol) in HCl (4M in dioxane, 3 mL) was stirred at roomtemperature for 3 h. The reaction mixture was concentrated in vacuo togive 1-(oxazol-2-yl)-4-phenylbutan-1-amine (60 mg, quant.). LCMSm/z=217.2 [M+H]⁺.

Synthesis of 4-phenyl-1-(pyridin-2-yl)butan-1-amine

Step 1: (S)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamide

A mixture of picolinaldehyde (3.0 g, 28.0 mmol),(S)-2-methylpropane-2-sulfinamide (4.06 g, 33.6 mmol) and Ti(OEt)₄ (12.8g, 56 mmol) in THF (50 mL) was stirred at room temperature overnight.Water was then added and the mixture extracted with EtOAc three times.The combined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed and the residue purified by silicacolumn chromatography (10% EtOAc/PE) to afford(S,E)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamide (1.1 g,21%): ¹H NMR (400 MHz, CD₃OD) δ 8.72 (ddd, J=4.9, 1.7, 0.9 Hz, 1H), 8.62(s, 1H), 8.13 (dt, J=8.0, 1.1 Hz, 1H), 8.00 (td, J=7.7, 1.7 Hz, 1H),7.58 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 1.29 (s, 9H).

Step 2:(S)-2-methyl-N-(4-phenyl-1-(pyridin-2-yl)butyl)propane-2-sulfinamide

To a solution of(S)-2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamide (300 mg, 1.4mmol) in dry THF was added (3-phenylpropyl)magnesium bromide (466 mg,2.1 mmol) dropwise at −78° C. under N₂. The reaction mixture was stirredat this temperature for 2 hours. The reaction was quenched with sat. aq.NH₄Cl solution and extracted with EtOAc three times. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Theresidue was concentrated and purified by silica column chromatography(5% MeOH/DCM) to give(S)-2-methyl-N-(4-phenyl-1-(pyridin-2-yl)butyl)propane-2-sulfinamide (86mg, 18%) as a mixture of diastereomers (2/5). ¹H NMR (400 MHz, CD₃OD) δ8.48 (ddd, J=4.9, 1.7, 1.0 Hz, 1H), 7.80 (qd, J=7.6, 1.8 Hz, 1H), 7.44(ddt, J=10.8, 8.0, 1.1 Hz, 1H), 7.33-7.27 (m, 1H), 7.26-7.18 (m, 2H),7.13 (td, J=6.1, 5.6, 2.9 Hz, 3H), 4.47-4.37 (m, 1H), 2.62 (t, J=7.5 Hz,2H), 2.02-1.54 (m, 4H), 1.19 (s, 9H, major isomer), 1.15 (s, 9H, minorisomer).

Step 3: 4-phenyl-1-(pyridin-2-yl)butan-1-amine

A solution of(S)-2-methyl-N-(4-phenyl-1-(pyridin-2-yl)butyl)propane-2-sulfinamide (30mg, 0.09 mmol) in HCl (4 M in dioxane, 2 mL) was stirred at roomtemperature for 3 h. The reaction mixture was concentrated to afford4-phenyl-1-(pyridin-2-yl)butan-1-amine which was used directly.

Synthesis of 4-phenyl-1-(pyrimidin-2-yl)butan-1-amine

Step 1: (S)-2-methyl-N-(pyrimidin-2-ylmethylene)propane-2-sulfinamide

(S)-2-methylpropane-2-sulfinamide (353 mg, 2.91 mmol) was added to asolution of pyrimidine-2-carbaldehyde (300 mg, 2.78 mmol) and KHSO₄ (397mg, 2.91 mmol) in toluene (20 mL) and the mixture was heated at 50° C.for 14 h. The reaction mixture was concentrated in vacuo and the residuepurified by silica column chromatography (30% EtOAc/PE) to give(S)-2-methyl-N-(pyrimidin-2-ylmethylene)propane-2-sulfinamide (330 mg,56%). LCMS m/z=212.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 9.00 (d, J=4.8Hz, 2H), 8.61 (s, 1H), 7.61 (t, J=4.8 Hz, 1H), 1.31 (s, 9H).

Step 2:(S)-2-methyl-N-(4-phenyl-1-(pyrimidin-2-yl)butyl)propane-2-sulfinamide

To a solution of(S)-2-methyl-N-(pyrimidin-2-ylmethylene)propane-2-sulfinamide (130 mg,0.62 mmol) in THF (3.0 mL) was added (3-phenylpropyl)magnesium bromide(1M in THF, 2.0 mL) at −78° C. under N₂. The mixture stirred at −78° C.for 10 min then allowed to warm to room temperature and stirringcontinued for 2 h. The reaction mixture was concentrated in vacuo andthe residue purified by silica column chromatography (50% EtOAc/PE) togive(S)-2-methyl-N-(4-phenyl-1-(pyrimidin-2-yl)butyl)propane-2-sulfinamide(54 mg, 26%).

Step 3: 4-phenyl-1-(pyrimidin-2-yl)butan-1-amine

A solution of(S)-2-methyl-N-(4-phenyl-1-(pyrimidin-2-yl)butyl)propane-2-sulfinamide(54 mg, 0.16 mmol) in HCl (4 M in dioxane, 2 mL) was stirred at roomtemperature for 1 h. The reaction mixture was concentrated in vacuo togive 4-phenyl-1-(pyrimidin-2-yl)butan-1-amine4-phenyl-1-(pyrimidin-2-yl)butan-1-amine (37 mg, quant.) which was useddirectly.

Synthesis of 3-methoxy-4-(trifluoromethoxy)benzoic acid

H₂O₂ (72 mg, 1.19 mmol) was added to a solution of3-methoxy-4-(trifluoromethoxy)benzaldehyde (80 mg, 0.36 mmol), NaH₂PO₄(282 mg, 1.19 mmol) and NaClO (164 mg, 1.19 mmol) in DMSO/H₂O (2.0mL/0.5 mL). The solution was stirred at room temperature for 5 h. Waterwas added and pH adjusted to ˜1 by addition of 1M HCl. The aqueous wasextracted with EtOAc three times. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. The residue wasconcentrated and used without further purification. LCMS m/z=234.9[M−H]⁻.

Synthesis of 1-(1H-indol-3-yl)cyclopropane-1-carboxylic acid

Step 1: 1-(1H-indol-3-yl)cyclopropane-1-carbonitrile

A solution of 2-(1H-indol-3-yl)acetonitrile (500 mg, 3.20 mmol) in THFwas treated with LDA (2M in THF, 6.4 mL, 12.8 mmol) at −30° C. Thesolution was allowed to warm to −5° C. and stirred for 30 min, thencooled to −30° C. and 1-bromo-2-chloroethane (550 mg, 3.84 mmol) wasadded dropwise. The reaction mixture was stirred at room temperature for2 h. Water was added and the pH adjusted to ˜1 by addition of 1M HCl.The aqueous was extracted with EtOAc three times and the combinedorganic layers washed with, water, brine and dried over Na₂SO₄. Theresidue after concentration was purified by silica gel column (20%EtOAc/PE) to afford 1-(1H-indol-3-yl)cyclopropane-1-carbonitrile (235mg, 40%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H),7.72-7.66 (m, 1H), 7.43-7.35 (m, 2H), 7.19-7.05 (m, 2H), 1.69-1.56 (m,2H), 1.41-1.28 (m, 2H).

Step 2: 1-(1H-indol-3-yl)cyclopropane-1-carboxylic acid

To a solution of 1-(1H-indol-3-yl)cyclopropane-1-carbonitrile (40 mg,0.22 mmol) in DMSO (2 mL) was added NaOH (35.2 mg, 0.88 mmol). Themixture was heated at 70° C. overnight. Water was added and pH adjustedto ˜1 by addition of 1M HCl. The aqueous was extracted with EtOAc threetimes and the combined organic layers were washed with water, brine anddried over Na₂SO₄. The solvent was removed to afford1-(1H-indol-3-yl)cyclopropane-1-carboxylic acid (43 mg, 97%) as acolorless oil, which was used directly.

Synthesis of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylicacid

Step 1: methyl 3-methoxy-4-((2-methylallyl)oxy)benzoate

2-methylprop-2-en-1-ol (396 mg, 5.49 mmol) was added to a solution ofmethyl 4-hydroxy-3-methoxybenzoate (1 g, 5.49 mmol), DIAD (258 mg, 5.49mmol) and PPh₃ (1.44 g, 5.49 mmol) in THF (8.0 mL). The reaction mixturewas stirred at room temperature for 14 h. The solvent was removed andthe residue purified by silica gel column (3% EtOAc/PE) to afford methyl3-methoxy-4-((2-methylallyl)oxy)benzoate (1 g, 77%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (dd, J=8.4, 2.4 Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.05 (s, 1H), 4.96 (s, 1H), 4.53 (s,2H), 3.82 (s, 3H), 3.81 (s, 3H), 1.76 (s, 3H).

Step 2: methyl 4-hydroxy-3-methoxy-5-(2-methylallyl)benzoate

Methyl 3-methoxy-4-((2-methylallyl)oxy)benzoate (100 mg, 0.42 mmol) wasdissolved in NMP (1.5 mL) and the solution heated at 205° C. for 7 h.The reaction was allowed to cool, water added and the aqueous extractedwith EtOAc three times. The combined organic layers were washed withwater, brine and dried over Na₂SO₄. The residue was concentrated andpurified by prep-TLC (5% MeOH/DCM) to afford methyl4-hydroxy-3-methoxy-5-(2-methylallyl)benzoate (80 mg, 80%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 7.42-7.29 (m, 2H), 4.75(s, 1H), 4.61 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.28 (s, 2H), 1.64(s, 3H).

Step 3: methyl7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate

To a solution of methyl 4-hydroxy-3-methoxy-5-(2-methylallyl)benzoate(60 mg, 0.25 mmol) in DCM (1.5 mL) was added formic acid (0.5 mL). Theresulting mixture was heated at 45° C. for 14 h in a sealed tube. Thesolvent was removed and the residue purified by prep-TLC (7% MeOH/DCM)to afford methyl7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate (55 mg, 92%)as a white oil. LCMS m/z=237.0 [M+H]⁺.

Step 4: 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid

NaOH (18.6 mg, 0.47 mmol) was added to a solution of methyl7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylate (55 mg, 0.23mmol) in a mixture of MeOH (2 mL) and H₂O (0.4 mL). The reaction mixturewas stirred at room temperature for 14 h. Water was added and the pHadjusted to ˜1 by addition of 1M HCl. The aqueous was extracted withEtOAc three times and the combined organic layers were washed withwater, brine and dried over Na₂SO₄. The solvent was removed to afford7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (205 mg,quant.) which was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 7.43 (d, J=1.6 Hz, 1H), 7.35 (d, J=1.6 Hz, 1H), 3.78 (s, 3H),3.04 (s, 2H), 1.42 (s, 6H).

Synthesis ofisopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylicacid

Step 1: methyl 4-(isopropylamino)-3-nitrobenzoate

To a solution of propan-2-amine (274 mg, 4.64 mmol) in THF (5 mL) wasadded methyl 4-chloro-3-nitrobenzoate (500 mg, 2.32 mmol) and Et₃N (704mg, 6.96 mmol). The mixture was stirred at room temperature overnight.Water was added and the aqueous extracted with EtOAc three times. Thecombined organic layers were washed with water, brine and dried overNa₂SO₄. The crude obtained, after concentration, was purified by silicagel column (20% EtOAc/PE) to afford methyl4-(isopropylamino)-3-nitrobenzoate (552 mg, quant.). LCMS m/z=239.2[M+H]⁺.

Step 2: methyl 3-amino-4-(isopropylamino)benzoate

To a solution of methyl 4-(isopropylamino)-3-nitrobenzoate (552 mg, 2.32mmol) in MeOH (5 mL) was added Pd/C (10%, 52 mg). The mixture wasstirred at room temperature overnight under an atmosphere of H₂. Thereaction mixture was filtered through celite and the filtrate wasconcentrated under reduced pressure to afford methyl3-amino-4-(isopropylamino)benzoate (442 mg, 92%). LCMS m/z=209.2 [M+H]⁺.

Step 3: methyl1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

To a solution of methyl 3-amino-4-(isopropylamino)benzoate (370 mg, 1.78mmol) in dioxane (4 mL) was added CDI (346 mg, 2.13 mmol) and thereaction mixture stirred at room temperature overnight. Water was addedand the aqueous extracted with EtOAc three times. The combined organiclayers were washed with water, brine, dried over Na₂SO₄ and concentratedin vacuo. The crude was purified by silica gel column (5% MeOH/DCM) toafford methyl1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (224mg, 54%).

Step 4: methyl1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate

To a solution of methyl1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (100mg, 0.43 mmol) in DMF (2 mL) at RT was added NaH (51 mg, 1.28 mmol). Themixture was stirred for 30 min then MeI (91 mg, 0.64 mmol) was added.The reaction mixture was then stirred for a further 4 h. Water was addedand the aqueous extracted with EtOAc three times. The combined organiclayers were washed with water, brine, dried over Na₂SO₄ and concentratedin vacuo. The crude was purified by silica gel column (3% MeOH/DCM) toafford methyl1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate(93 mg, 88%). LCMS m/z=249.2 [M+H]⁺.

Step 5:isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylicacid

To a solution of methyl1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate(93 mg, 0.37 mmol) in MeOH (1 mL) was added NaOH (10%, 1 mL) and thereaction stirred for 2 h. Water was added and the pH adjusted to ˜1 byaddition of 1 M HCl. The aqueous was extracted with EtOAc three timesand the combined organic layers were washed with water, brine, driedover Na₂SO₄ and concentrated in vacuo to affordisopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylicacid (86 mg, quant.).

Synthesis of 1-isopropyl-3-methoxy-1H-indazole-6-carboxylic acid

Step 1: methyl 3-iodo-1-isopropyl-1H-indazole-6-carboxylate

To a solution of methyl 3-iodo-1H-indazole-6-carboxylate (300 mg, 1mmol) in DMF (5 mL) was added 2-iodopropane (336 mg, 2 mmol) and Cs₂CO₃(972 mg, 3 mmol). The resulting mixture was stirred at room temperatureovernight. Water was added and the aqueous extracted with EtOAc threetimes. The combined organic layers were washed with water, brine anddried over Na₂SO₄. The residue was concentrated and purified by silicagel column (20% EtOAc/PE) to afford methyl3-iodo-1-isopropyl-1H-indazole-6-carboxylate (280 mg, 81%) as a yellowoil. LCMS m/z=345.0 [M+H]⁺.

Step 2: methyl 1-isopropyl-3-methoxy-JH-indazole-6-carboxylate

To a solution of methyl 3-iodo-1-isopropyl-1H-indazole-6-carboxylate(150 mg, 0.43 mmol) in MeOH (1 mL) was added Cs₂CO₃ (281 mg, 0.87 mmol),3,4,7,8-tetramethyl-1,10-phenanthroline (20 mg, 0.085 mmol) and CuI (8mg, 0.043 mmol). The resulting mixture was heated at 140° C. for 2 h ina microwave reactor. Water was added and the aqueous extracted withEtOAc three times. The combined organic layers were washed with water,brine and dried over Na₂SO₄. The residue was concentrated and purifiedby silica gel column (12% EtOAc/PE) to afford methyl1-isopropyl-3-methoxy-1H-indazole-6-carboxylate (45 mg, 42%) as a yellowoil. LCMS m/z=249.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (dd, J=1.6,0.8 Hz, 1H), 7.97 (dd, J=9.0, 1.6 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H),4.83-4.77 (m, 1H), 4.09 (s, 3H), 3.91 (s, 3H), 1.49 (d, J=6.4 Hz, 6H).

Step 3: 1-isopropyl-3-methoxy-JH-indazole-6-carboxylic acid

To a solution of methyl 1-isopropyl-3-methoxy-1H-indazole-6-carboxylate(45 mg, 0.18 mmol) in MeOH (1 mL) was added 10% aq NaOH (1 mL) and thereaction stirred at room temperature for 3 h. The solvent was removedand water added. The pH was adjusted to ˜1 by addition of 1 M HCl andthe aqueous extracted with EtOAc three times. The combined organiclayers were washed with water, brine, dried over Na₂SO₄ and concentratedto afford 1-isopropyl-3-methoxy-1H-indazole-6-carboxylic acid (30 mg,71%) as a colourless oil. LCMS m/z=235.1 [M+H]⁺.

Synthesis of 7-isopropoxybenzofuran-4-carboxylic acid

Step 1: benzofuran-7-ol

To a solution of BBr₃ (1M in DCM, 2 mL, 2 mmol) at −78° C. was added asolution of 7-methoxybenzofuran (150 mg, 1 mmol) in DCM (2 mL) dropwise.The resulting mixture was allowed to warm to room temperature andstirred for 4 hours under N₂. Water was added and the aqueous extractedwith diethylether three times. The combined organic layers were washedwith water, brine, dried over Na₂SO₄ and concentrated. The residue waspurified by prep-TLC (30% EtOAc/PE) to afford benzofuran-7-ol (55 mg,31%) as a black oil. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=2.2 Hz, 1H),7.20-7.08 (m, 2H), 6.84 (dd, J=7.8, 1.2 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H).

Step 2: 7-isopropoxybenzofuran

To a solution of benzofuran-7-ol (50 mg, 0.37 mmol) in DMF (1 mL) wasadded 2-iodopropane (76 mg, 0.45 mmol) and K₂CO₃ (155 mg, 1.1 mmol). Theresulting mixture was stirred at room temperature for 4 hours. Thesolvent was removed in vacuo and the residue purified by prep-TLC (30%EtOAc/PE) to afford 7-isopropoxybenzofuran (44 mg, 68%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=2.2 Hz, 1H), 7.20-7.09 (m, 2H),6.82 (dd, J=7.8, 1.2 Hz, 1H), 6.75 (d, J=2.2 Hz, 1H), 4.80 (p, J=6.0 Hz,1H), 1.43 (d, J=6.0 Hz, 6H).

Step 3: 7-isopropoxybenzofuran-4-carbaldehyde

To a solution of 7-isopropoxybenzofuran (44 mg, 0.25 mmol) in DMF (1 mL)was added POCl₃ (230 mg, 1.5 mmol) and the reaction heated at 100° C.for 4 hours under N₂. The reaction was cooled to room temperature andthe mixture was poured into saturated Na₂CO₃ solution and extracted withether three times. The combined organic layers were washed with water,brine and dried over Na₂SO₄. The residue was purified by prep-TLC (30%EtOAc/PE) to afford 7-isopropoxybenzofuran-4-carbaldehyde (40 mg, 78%)as a yellow oil. LCMS m/z=205.1 [M+H]⁺.

Step 4: 7-isopropoxybenzofuran-4-carboxylic acid

To a solution of 7-isopropoxybenzofuran-4-carbaldehyde (40 mg, 0.2 mmol)in a mixture of DMSO (1 mL) and H₂O (1 mL) was added NaClO₂ (115 mg, 1.0mmol), NaH₂PO₄ (160 mg, 1.0 mmol) and 30% H₂O₂ (113 mg, 1.0 mmol). Theresulting mixture was stirred at room temperature for 4 hours under N₂.Water was added and the pH adjusted to ˜1 by addition of 1M HCl. Theaqueous was extracted with EtOAc three times. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. The residuewas purified by prep-TLC (20% EtOAc/PE) to afford7-isopropoxybenzofuran-4-carboxylic acid (20 mg, 45%) as a white solid.LCMS m/z=221.0 [M+H]⁺.

Synthesis of methyl O-benzyl-L-allothreoninate

Step 1: (tert-butoxycarbonyl)-L-allothreonine

To a solution of L-allothreonine (1.0 g, 8.4 mmol) and K₂CO₃ (2.3 g,16.8 mmol) in a mixture of THF (10 mL) and H₂O (2 mL) at 0° C. was added(Boc)₂O (2.0 g, 9.2 mmol). The resulting mixture was stirred for 5hours, then water was added and the aqueous extracted with Et₂O threetimes and the organic layers discarded. The pH of the aqueous layer wasadjusted to ˜1 by addition of 1M HCl and extracted with 20% MeOH/DCMthree times. The combined organic layers were washed with water andbrine, dried over Na₂SO₄ and concentrated to afford(tert-butoxycarbonyl)-L-allothreonine (1.0 g, 55%). LCMS m/z=164.1[M−^(t)Butyl+H]⁺.

Step 2: O-benzyl-N-(tert-butoxycarbonyl)-L-allothreonine

To a solution of (tert-butoxycarbonyl)-L-allothreonine (2.0 g, 9.12mmol) in DMF (20 mL) at 0° C. was added NaH (728 mg, 18.2 mmol) and theresulting mixture stirred for 30 minutes. Benzyl bromide (1.1 mL, 9.12mmol) was then added and the reaction mixture stirred for another 3hours at room temperature. Water was added and the aqueous extractedwith EtOAc three times. The combined organic layers were washed withwater, brine and dried over Na₂SO₄. The residue was concentrated andpurified by reverse-phase column to affordO-benzyl-N-(tert-butoxycarbonyl)-L-allothreonine (1.7 g, 61%). LCMSm/z=254.2 [M−^(t)Butyl+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H),7.39-7.21 (m, 5H), 7.01 (d, J=8.8 Hz, 1H), 4.47 (s, 2H), 4.28 (dd,J=9.0, 5.6 Hz, 1H), 3.88-3.77 (m, 1H), 1.39 (s, 9H), 1.11 (d, J=6.4 Hz,3H).

Step 3: methyl O-benzyl-N-(tert-butoxycarbonyl)-L-allothreoninate

To a solution of O-benzyl-N-(tert-butoxycarbonyl)-L-allothreonine (480mg, 1.55 mmol) and K₂CO₃ (429 mg, 3.10 mmol) in DMF (15 mL) was addedCH₃I (330.7 mg, 2.33 mmol) and the reaction stirred for 4 hours. Waterwas added and the aqueous extracted with EtOAc three times. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Theresidue was concentrated and purified by silica gel column (20%EtOAc/PE) to afford methylO-benzyl-N-(tert-butoxycarbonyl)-L-allothreoninate (498 mg, 99%) as acolourless oil. LCMS m/z=268.2 [M−^(t)Butyl+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ 7.37-7.26 (m, 5H), 5.25 (d, J=8.8 Hz, 1H), 4.60-4.49 (m, 3H),3.97-3.80 (m, 1H), 3.75 (s, 3H), 1.43 (s, 9H), 1.23 (d, J=6.4 Hz, 3H).

Step 4: methyl O-benzyl-L-allothreoninate

To a solution of methylO-benzyl-N-(tert-butoxycarbonyl)-L-allothreoninate (480 mg, 1.49 mmol)in DCM (5 mL) was added TFA (2.5 mL). The mixture was stirred for 4hours. The solvent was removed to afford methylO-benzyl-L-allothreoninate (400 mg, quant). LCMS m/z=224.2 [M+H]⁺.

Synthesis of (9H-fluoren-9-yl)methyl(S)-(5-(2-amino-5-(3-hydroxyphenyl)pentanamido)pentyl)carbamate

Step 1: tert-butyl(S)-(1-((5-azidopentyl)amino)-1-oxopent-4-en-2-yl)carbamate

A solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (517mg, 2.4 mmol), 5-azidopentan-1-amine (280 mg, 2.18 mmol), EDCI (630 mg,3.3 mmol), HOBt (443 mg, 3.3 mmol) and DIEA (1.12 g, 8.8 mmol) in DMA (5mL) was stirred at room temperature overnight. Water was added and theaqueous extracted with EtOAc. The combined organic layers were washedwith water and brine and dried over Na₂SO₄. The residue afterconcentration was purified by silica gel column (50% EtOAc/PE) to affordtert-butyl (S)-(1-((5-azidopentyl)amino)-1-oxopent-4-en-2-yl)carbamate(330 mg, 46%) as a yellow oil. LCMS m/z=326.2 [M+H]⁺. Step 2: tert-butyl(S,E)-(1-((5-azidopentyl)amino)-5-(3-(benzyloxy)phenyl)-1-oxopent-4-en-2-yl)carbamateTo a solution of tert-butyl(S)-(1-((5-azidopentyl)amino)-1-oxopent-4-en-2-yl)carbamate (1.07 g, 3.3mmol) and 1-(benzyloxy)-3-iodobenzene (1.02 g, 3.3 mmol) in a mixture ofDMF (8 mL) and H₂O (2 mL) was added Pd(OAc)₂ (73 mg, 0.33 mmol) andNaHCO₃ (1.1 g, 13.2 mmol). The reaction mixture was heated at 75° C. for4 h. Water was added and the aqueous extracted with EtOAc. The combinedorganic layers were washed with water and brine and dried over Na₂SO₄.The residue after concentration was purified by silica gel column (50%EtOAc/PE) to afford tert-butyl(S,E)-(1-((5-azidopentyl)amino)-5-(3-(benzyloxy)phenyl)-1-oxopent-4-en-2-yl)carbamate(1.38 g, 82%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.46-7.40 (m,2H), 7.39-7.27 (m, 3H), 7.19 (t, J=8.0 Hz, 1H), 7.00 (t, J=2.0 Hz, 1H),6.95 (d, J=7.6 Hz, 1H), 6.85 (dd, J=8.0, 2.4 Hz, 1H), 6.47-6.38 (m, 1H),6.24-6.12 (m, 1H), 5.07 (s, 2H), 4.16-4.07 (m, 1H), 3.29-3.20 (m, 1H),3.17-3.06 (m, 3H), 2.68-2.43 (m, 2H), 1.51-1.39 (m, 12H), 1.37-1.27 (m,3H).

Step 3: tert-butyl(S)-(1-(5-aminopentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)carbamate

To a solution of tert-butyl(S,E)-(1-((5-azidopentyl)amino)-5-(3-(benzyloxy)phenyl)-1-oxopent-4-en-2-yl)carbamate(1.4 g, 2.76 mmol) in MeOH (8 mL) was added Pd/C (10%, 200 mg). Thereaction mixture was stirred at room temperature overnight. The solutionwas filtered through celite and the filtrate was concentrated to affordtert-butyl(S)-(1-((5-aminopentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)carbamate(970 mg, 89%) which was used in next step directly. ¹H NMR (400 MHz,CD₃OD) δ 7.05 (t, J=8.0 Hz, 1H), 6.66-6.56 (m, 3H), 4.03-3.90 (m, 1H),3.26-3.09 (m, 2H), 2.67-2.50 (m, 4H), 1.73-1.48 (m, 7H), 1.44 (s, 9H),1.40-1.28 (m, 3H).

Step 4: tert-butyl(S)-(1-((5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)carbamate

To a solution of tert-butyl(S)-(1-((5-aminopentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)carbamate(200 mg, 0.5 mmol) and FmocOSu (189 mg, 0.55 mmol) in a mixture of THF(4 mL) and H₂O (1 mL) was added NaHCO₃(85 mg, 1 mmol). The reactionmixture was stirred at room temperature for 4 h. Water was added and theaqueous extracted with EtOAc. The combined organic layers were washedwith water, brine and dried over Na₂SO₄. The residue after concentrationwas purified by silica gel column (50% EtOAc/PE) to afford tert-butyl(S)-(1-((5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)carbamate(137 mg, 44%) as a white solid. LCMS m/z=616.2 [M+H]⁺

Step 5: (9H-fluoren-9-yl)methyl(S)-(5-(2-amino-5-(3-hydroxyphenyl)pentanamido)pentyl)carbamate

To a solution of tert-butyl(S)-(1-((5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)carbamate(50 mg, 0.08 mmol) in DCM (2 mL) was added TFA (2 mL) and the reactionmixture was stirred at room temperature for 2 h. The solvent was removedunder reduced pressure to afford the product (57 mg, quant.) as a whitesolid. LCMS m/z=516.2 [M+H]⁺.

Synthesis of (2S,3S)-2-amino-N-(5-azidopentyl)-3-(benzyloxy)butanamide

Step 1: tert-butyl((2S,3S)-1-(5-azidopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate

To a solution of O-benzyl-N-(tert-butoxycarbonyl)-L-allothreonine (220mg, 0.71 mmol) in DMA (1 mL) was added 5-azidopentan-1-amine (100 mg,0.78 mmol), EDCI (205 mg, 1.07 mmol), HOBt (144 mg, 1.07 mmol) and DIEA(460 mg, 3.56 mmol). The resulting mixture was stirred at roomtemperature for 4 hours under N₂. Water was added and the aqueousextracted with EtOAc three times. The combined organic layers werewashed with water and brine and dried over Na₂SO₄. The residue obtainedafter concentration was purified by silica gel column (30% EtOAc/PE) toafford tert-butyl ((2 S,3S)-1-((5-azidopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate (220mg, 73%) as a yellow oil. LCMS m/z=420.3 [M+H]⁺.

Step 2: (2S,3S)-2-amino-N-(5-azidopentyl)-3-(benzyloxy)butanamide

To a solution of tert-butyl((2S,3S)-1-((5-azidopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)carbamate(244 mg, 0.58 mmol) in MeOH (1 mL) was added HCl (4M in dixoane, 2 mL).The resulting mixture was stirred at room temperature for 1 h. Thesolvent was removed to afford (2 S,3S)-2-amino-N-(5-azidopentyl)-3-(benzyloxy)butanamide (220 mg, quant.)LCMS m/z=320.3 [M+H]⁺.

Example 2: Synthesis of Exemplary Compounds Synthesis of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)-N-((5)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-1

Step 1: 2-(tert-butyl) 7-ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate

To a solution of 2-(tert-butyl) 7-ethyloctahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate (Int-1, 6.4 g,21.5 mmol) in DMF (60 mL) was added 2-(6-chloro-1H-indol-3-yl)aceticacid (5.9 g, 28.2 mmol), EDCI (6.8 g, 35.3 mmol), HOBt (4.8 g, 35.3mmol) and DIPEA (9.1 g, 70.5 mmol). The resulting mixture was stirred atroom temperature for 14 h. Water was then added and the aqueous layerwas extracted with EtOAc. The combined organic layers were washed withwater and brine, dried over Na₂SO₄ and the solvent removed in vacuo. Theresidue was purified by column chromatography (2% MeOH/DCM) to affordthe product (5.3 g, 46%) as a white solid. LCMS m/z=490.0 [M+H]⁺; ¹H NMR(400 MHz, CD₃OD) δ 7.64-7.50 (m, 1H), 7.37-7.31 (m, 1H), 7.24-7.14 (m,1H), 7.04-6.96 (m, 1H), 4.68-3.66 (m, 5H), 3.52-3.37 (m, 1H), 3.29-2.06(m, 7H), 1.98-1.77 (m, 1H), 1.46-1.35 (m, 9H), 1.24 (t, J=7.2 Hz, 3H).Step 2:2-(tert-butoxycarbonyl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid

To a solution of 2-(tert-butyl) 7-ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate(2.0 g, 4.1 mmol) in MeOH (20 mL) was added aqueous NaOH (1M, 4.1 mL).The resulting mixture was stirred for 3 h then the solvent removed undervacuum. The residue obtained was diluted with water and and the pHadjusted to ˜1 by addition of 1M HCl. The aqueous layer was extractedwith EtOAc three times and the combined organic layers washed with waterand brine, dried over Na₂SO₄ and concentrated to afford the product (1.7g, 90%) as a white solid. LCMS m/z=462.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD)δ 7.63-7.47 (m, 1H), 7.37-7.31 (m, 1H), 7.25-7.15 (m, 1H), 7.05-6.96 (m,1H), 4.71-4.11 (m, 2H), 4.07-3.70 (m, 2H), 3.54-3.36 (m, 1H), 3.29-2.04(m, 7H), 2.00-1.77 (m, 1H), 1.47-1.35 (m, 9H).

Step 3: tert-butyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

In a similar manner to the procedure reported for Step 1, the couplingof2-(tert-butoxycarbonyl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid and (S)-2-amino-N-methyl-5-phenylpentanamide gave the product (1.8g, quant.) after column chromatography (2% MeOH/DCM) as a white solid.LCMS m/z=650.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.68-6.87 (m, 9H),4.53-3.66 (m, 5H), 3.56-3.38 (m, 1H), 3.28-2.77 (m, 4H), 2.76-1.98 (m,9H), 1.87-1.51 (m, 4H), 1.50-1.33 (m, 9H).

Step 4:5-(2-(6-chloro-1H-indol-3-yl)acetyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamidehydrochloride

To a solution of tert-butyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate(1.8 g, 2.77 mmol) in a mixture of DCM and MeOH (20 mL/10 mL) was addedHCl in dioxane (4M, 6 mL). The resulting mixture was stirred for 3 h,then the solvent removed under reduced pressure to afford the product(1.7 g, quant.). LCMS m/z=550.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ7.68-6.89 (m, 9H), 4.49-3.73 (m, 5H), 3.61-3.34 (m, 1H), 3.30-2.81 (m,4H), 2.78-2.28 (m, 8H), 1.89-1.55 (m, 4H).

Step 5:5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(I-1)

A mixture of the product of Step 4 (73 mg, 0.12 mmol),4-isopropoxy-3-methoxybenzoic acid (27 mg, 0.15 mmol), EDCI (36 mg 0.19mmol), HOBt (20 mg, 0.15 mmol) and DIEA (65 mg, 0.5 mmol) in DMF (2.0mL) was stirred overnight. The reaction mixture was diluted with waterand extracted with EtOAc three times. The combined organic layers werewashed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography (3.3% MeOH/DCM)to give I-1 (33.4 mg, 39%) as a white solid. LCMS m/z=712.4 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ 7.66-6.77 (m, 13H), 4.79-3.35 (m, 9H), 3.29-2.98(m, 2H), 2.98-2.76 (m, 1H), 2.76-2.48 (m, 6H), 2.43 (ddd, J=12.4, 7.2,3.8 Hz, 1H), 2.37-1.99 (m, 1H), 1.97-1.43 (m, 4H), 1.42-1.22 (m, 7H).

The compounds listed in Table 2 were synthesized using analogous methodsto those shown for I-1, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers unless indicated otherwise.

TABLE 2 Compounds made by a method analogous to I-1 # ¹H NMRChromatography conditions, if applicable LCMS I-2 ¹H NMR (400 MHz,CD₃OD) δ 7.71-6.80 (m, 12H), 4.61-3.34 (m, m/z = 707.3 7H), 3.28-2.78(m, 2H), 2.78-2.58 (m, 5H), 2.57-2.34 (m, 6H), 2.30- [M + H]⁺ 1.98 (m,1H), 1.84-0.86 (m, 5H). I-3 ¹H NMR (400 MHz, CD₃OD) δ 7.82-6.86 (m,12H), 6.57-6.39 (m, m/z = 708.3 1H), 4.60-4.15 (m, 2H), 4.15-3.69 (m,3H), 3.69-3.39 (m, 3H), 3.27- [M + H]⁺ 2.97 (m, 2H), 2.93-2.34 (m, 11H),2.35-2.18 (m, 1H), 2.09-1.34 (m, 4H), 1.24-1.88 (m, 1H). I-4 ¹H NMR (400MHz, CD₃OD) δ 7.55-7.76 (m, 13H), 4.51-4.30 (m, m/z = 670.3 1H),4.28-3.84 (m, 4H), 3.71-3.64 (m, 1H), 3.55-3.37 (m, 2H), 3.27- [M + H]⁺2.80 (m, 3H), 2.76-2.60 (m, 6H), 2.45-2.07 (m, 2H), 1.65-1.28 (m, 5H).I-5 ¹H NMR (400 MHz, CD₃OD) δ 7.66-6.76 (m, 13H), 4.44-3.72 (m, m/z =684.3 8H), 3.68-3.40 (m, 3H), 3.13-2.95 (m, 1H), 2.78-2.56 (m, 6H),2.46- [M + H]⁺ 2.37 (m, 1H), 2.21-2.00 (m, 1H), 1.82-1.49 (m, 4H),1.41-1.32 (m, 2H). I-6 ¹H NMR (400 MHz, CD₃OD) δ 7.65-6.91 (m, 13H),4.57-4.36 (m m/z = 710.3 1H), 4.35-3.74 (m, 5H), 3.70-3.36 (m, 4H),3.30-2.78 (m, 3H), 2.77- [M + H]⁺ 1.99 (m, 9H), 1.80-1.37 (m, 4H),0.88-0.58 (m, 4H). I-7 ¹H NMR (400 MHz, CD₃OD) δ 7.67-6.80 (m, 13H),4.61-3.72 (m, m/z = 726.4 6H), 3.72-3.34 (m, 4H), 3.30-2.75 (m, 3H),2.75-1.92 (m, 9H), 1.85- [M + H]⁺ 1.33 (m, 4H), 1.24-0.88 (m, 7H). I-8¹H NMR (400 MHz, CD₃OD) δ 8.22-8.06 (m, 1H), 8.01-7.77 (m, 1H), m/z =694.3 7.65-6.78 (m, 11H), 4.62-4.06 (m, 3H), 4.05-3.33 (m, 7H), 3.30-[M + H]⁺ 3.01 (m, 2H), 3.00-1.83 (m, 10H), 1.81-1.34 (m, 4H). I-9 ¹H NMR(400 MHz, CD₃OD) δ 7.67-7.45 (m, 1H), 7.45-6.62 (m, m/z = 768.3 11H),4.63-3.35 (m, 14H), 3.29-2.33 (m, 11H),, 1.87-1.50 (m, 5H), [M + H]⁺1.05-0.73 (m, 1H), 0.58-0.35 (m, 2H), 0.19-0.05 (m, 2H). I-10 ¹H NMR(400 MHz, CD₃OD) δ 8.97-6.76 (m, 15H), 4.52-4.10 (m, m/z = 705.2 3H),3.94-3.72 (m, 3H), 3.64-3.35 (m, 3H), 3.30-2.83 (m, 2H), 2.86- [M + H]⁺2.28 (m, 8H), 2.08-2.00 (m, 1H), 1.77-1.41 (m, 3H), 1.12-0.90 (m, 1H).I-11 ¹H NMR (400 MHz, CD₃OD) δ 7.86-6.88 (m, 18H), 4.63-4.02 (m, m/z =730.3 2H), 3.88 (m, 2H), 3.74-3.34 (m, 3H), 3.27-2.94 (m, 2H), 2.93-1.91[M + H]⁺ (m, 9H), 1.87-1.22 (m, 5H). I-12 ¹H NMR (400 MHz, CD₃OD) δ7.92-6.68 (m, 13H), 4.63-3.84 (m, m/z = 694.2 7H), 3.83-3.33 (m, 3H),3.25-2.75 (m, 2H), 2.75-2.23 (m, 8H), 1.79- [M + H]⁺ 1.57 (m, 3H),1.54-1.35 (m, 1H). I-13 ¹H NMR (400 MHz, CD₃OD) δ 7.96-7.80 (m, 2H),7.56-7.48 (m, 4H), m/z = 721.2 7.38-6.92 (m, 8H), 4.53-4.45 (m, 1H),4.28-4.03 (m, 2H), 3.94- [M + H]⁺ 3.49 (m, 6H), 3.20-2.81 (m, 2H),2.78-2.33 (m, 7H), 2.20-2.03 (m, 1H), 1.71-1.50 (m, 4H), 1.36-1.25 (m,3H). I-14 ¹H NMR (400 MHz, CD₃OD) δ 8.74-8.52 (m, 2H), 7.87-6.84 (m, m/z= 731.3 15H), 4.70-3.87 (m, 5H), 3.85-3.33 (m, 4H), 3.29-2.81 (m, 3H),2.80- [M + H]⁺ 2.49 (m, 7H), 2.42-2.13 (m, 1H), 1.86-1.51 (m, 3H). I-15¹H NMR (400 MHz, CD₃OD) δ 8.92-6.92 (m, 12H), 4.56-4.46 (m, m/z = 680.31H), 4.39-4.30 (m, 1H), 4.21-4.06 (m, 1H), 3.94-3.78 (m, 3H), 3.63- [M +H]⁺ 3.40 (m, 3H), 3.30-2.91 (m, 2H), 2.74-2.68 (m, 8H), 2.35-2.00 (m,1H), 1.83-1.44 (m, 4H). I-16 ¹H NMR (400 MHz, CD₃OD) δ 8.72-8.33 (m,1H), 8.22-7.84 (m, 1H), m/z = 686.3 7.60-6.83 (m, 9H), 4.56-3.76 (m,9H), 3.73-3.43 (m, 3H), 3.23- [M + H]⁺ 2.76 (m, 2H), 2.75-2.55 (m, 6H),2.54-2.16 (m, 2H), 1.79-1.45 (m, 4H). I-17 ¹H NMR (400 MHz, CD₃OD) δ9.12-8.87 (m, 2H), 8.32-6.70 (m, m/z = 706.3 12H), 4.68-3.87 (m, 6H),3.85-3.40 (m, 4H), 3.30-3.02 (m, 2H), 3.01- [M + H]⁺ 2.63 (m, 6H),2.61-2.44 (m, 2H), 2.41-2.01 (m, 2H), 1.80-1.39 (m, 3H), 1.25-0.85 (m,1H). I-18 ¹H NMR (400 MHz, CD₃OD) δ 9.40-9.16 (m, 1H), 8.58-8.43 (m,1H), m/z = 705.3 8.16-6.58 (m, 13H), 4.53-3.87 (m, 5H), 3.64-3.41 (m,3H), 3.06- [M + H]⁺ 2.44 (m, 10H), 2.29-1.42 (m, 5H). I-19 ¹H NMR (400MHz, CD₃OD) δ 8.01-6.68 (m, 15H), 4.63-4.36 (m, m/z = 720.3 1H),4.36-3.81 (m, 5H), 3.80-3.35 (m, 3H), 3.19-1.89 (m, 10H), 1.80- [M + H]⁺1.40 (m, 4H). I-20 ¹H NMR (400 MHz, CD₃OD) δ 7.96-6.91 (m, 12H),4.78-4.17 (m, m/z = 685.3 4H), 4.06-3.34 (m, 6H), 3.24-2.16 (m, 10H),1.74-1.29 (m, 5H). [M + H]⁺ I-21 ¹H NMR (400 MHz, CD₃OD) δ 8.29-6.69 (m,11H), 4.56-3.41 (m, m/z = 686.3 11H), 3.27-2.76 (m, 2H), 2.75-2.46 (m,7H), 2.38-1.96 (m, 1H), 1.80- [M + H]⁺ 1.42 (m, 4H), 1.37-1.30 (m, 1H).I-22 ¹H NMR (400 MHz, CD₃OD) δ 7.63-6.88 (m, 12H), 4.54-3.84 (m, m/z =709.3 5H), 3.71-3.36 (m, 5H), 3.26-1.96 (m, 12H), 1.83-1.40 (m, 4H).[M + H]⁺ First eluting diastereomer purified by Prep-TLC (6% MeOH/DCM).Rf = 0.40 I-23 ¹H NMR (400 MHz, CD3OD) δ 7.67-6.79 (m, 12H), 4.66-3.39(m, m/z = 709.3 10H), 3.32-2.35 (m, 11H), 2.33-1.52 (m, 4H). [M + H]⁺Second eluting diastereomer purified by Prep-TLC (6% MeOH/DCM). Rf =0.32 I-24 ¹H NMR (400 MHz, CD₃OD) δ 7.61-6.92 (m, 12H), 4.59-4.27 (m,m/z = 746.3 3H), 4.89-3.80 (m, 3H), 3.69-3.40 (m, 3H), 3.23-3.01 (m,2H), 2.98- [M + H]⁺ 2.75 (m, 1H), 2.72-2.41 (m, 7H), 2.29-2.13 (m, 1H),1.78-1.55 (m, 3H), 1.43-1.24 (m, 8H). I-25 ¹H NMR (400 MHz, CD₃OD) δ7.67-6.91 (m, 13H), 4.62-3.35 (m, m/z = 738.3 8H), 3.29-2.80 (m, 3H),2.78-2.54 (m, 6H), 2.49-2.40 (m, 1H), 2.35- [M + H]⁺ 1.92 (m, 1H),1.82-1.56 (m, 3H), 1.38-1.28 (m, 1H). I-26 ¹H NMR (400 MHz, CD₃OD) δ7.82-7.77 (m, 2H), 7.56-6.74 (m, m/z = 734.3 13H), 4.20-4.00 (m, 3H),3.98-3.45 (m, 9H), 3.20-3.07 (m, 2H), 2.97- [M + H]⁺ 2.91 (m, 1H),2.74-2.29 (m, 8H), 1.84-1.27 (m, 5H). I-27 ¹H NMR (400 MHz, CD₃OD) δ9.31-6.60 (m, 15H), 4.78-3.34 (m, m/z = 720.4 9H), 3.28-2.81 (m, 2H),2.81-2.24 (m, 8H), 2.22-1.76 (m, 1H), 1.74- [M + H]⁺ 1.32 (m, 4H). I-28¹H NMR (400 MHz, CD₃OD) δ 8.17 (m, 1H), 7.70-6.76 (m, 12H), 4.58- m/z =694.4 4.36 (m, 1H), 4.35-4.06 (m, 2H), 4.04-3.57 (m, 5H), 3.56-3.35 (m,[M + H]⁺ 1H), 3.23-2.85 (m, 2H), 2.77-2.45 (m, 7H), 2.47-1.93 (m, 1H),1.87- 1.33 (m, 5H). I-29 ¹H NMR (400 MHz, CD₃OD) δ 8.12-6.24 (m, 11H),4.66-4.11 (m, m/z = 644.4 2H), 4.10-3.75 (m, 4H), 3.72-3.34 (m, 2H),3.24-2.80 (m, 2H), 2.79- [M + H]⁺ 2.03 (m, 9H), 1.87-1.37 (m, 6H). I-30¹H NMR (400 MHz, CD₃OD) δ 7.58-6.21 (m, 10H), 4.55-3.34 (m, m/z = 684.49H), 3.27-2.86 (m, 2H), 2.75-2.49 (m, 7H), 2.27-1.34 (m, 6H), 1.05- [M +H]⁺ 0.63 (m, 4H). I-31 ¹H NMR (400 MHz, CD₃OD) δ 7.99-6.80 (m, 12H),4.58-4.06 (m, m/z = 763.3 2H), 4.04-3.34 (m, 9H), 3.29-2.96 (m, 2H),2.94-2.35 (m, 9H), 2.31- [M + H]⁺ 1.34 (m, 4H). I-32 ¹H NMR (400 MHz,CD₃OD) δ 7.71-6.62 (m, 12H), 4.50-3.44 (m, m/z = 700.4 11H), 3.24-2.79(m, 3H), 2.77-1.87 (m, 9H), 1.81-1.34 (m, 7H). [M + H]⁺ I-33 ¹H NMR (400MHz, CD₃OD) δ 7.67-6.66 (m, 12H), 4.56-3.74 (m, m/z = 714.3 11H),3.70-3.41 (m, 3H), 3.27-2.79 (m, 3H), 2.74-2.00 (m, 9H), 1.81- [M + H]⁺1.49 (m, 3H). I-34 ¹H NMR (400 MHz, CD₃OD) δ 7.44-6.41 (m, 12H),4.38-3.20 (m, m/z = 700.4 11H), 3.09-2.57 (m, 3H), 2.56-2.29 (m, 7H),1.62-1.33 (m, 3H), 1.19- [M + H]⁺ 0.97 (m, 2H). I-35 ¹H NMR (400 MHz,CD₃OD) δ 7.61-6.89 (m, 18H), 4.54-3.37 (m, m/z = 746.4 8H), 3.26-2.82(m, 3H), 2.80-2.32 (m, 8H), 2.28-1.97 (m, 1H), 1.84- [M + H]⁺ 1.55 (m,3H) I-36 ¹H NMR (400 MHz, CD₃OD) δ 9.07-6.72 (m, 15H), 4.60-3.80 (m, m/z= 705.3 5H), 3.79-3.47 (m, 3H), 3.26-3.03 (m, 2H), 2.96-2.42 (m, 8H),2.36- [M + H]⁺ 1.97 (m, 2H), 1.84-1.47 (m, 3H), 1.15-0.90 (m, 1H). I-37¹H NMR (400 MHz, CD₃OD) δ 9.33-8.72 (m, 1H), 8.26-7.50 (m, 6H), m/z =705.3 7.41-6.77 (m, 8H), 4.62-3.42 (m, 8H), 3.21-2.97 (m, 1H), 2.91-2.39[M + H]⁺ (m, 8H), 2.28-2.10 (m, 1H), 1.87-1.43 (m, 4H), 1.22-0.84 (m,1H). I-38 ¹H NMR (400 MHz, CD₃OD) δ 7.65-6.70 (m, 13H), 4.66-3.37 (m,m/z = 707.3 10H), 3.25-2.83 (m, 2H), 2.78-2.32 (m, 11H), 2.30-2.14 (m,1H), [M + H]⁺ 1.92-1.42 (m, 4H). I-39 ¹H NMR (400 MHz, CD₃OD) δ7.73-6.12 (m, 10H), 4.56-3.39 (m, m/z = 672.4 12H), 3.24-1.93 (m, 14H),1.77-1.46 (m, 4H). [M + H]⁺ I-40 ¹H NMR (400 MHz, CD₃OD) δ 9.12-8.26 (m,3H), 7.99-6.61 (m, m/z = 695.3 10H), 4.61-3.47 (m, 9H), 3.27-2.84 (m,2H), 2.75-1.98 (m, 8H), 1.79- [M + H]⁺ 1.41 (m, 4H). I-41 ¹H NMR (400MHz, CD₃OD) δ 8.62-7.82 (m, 2H), 7.60-6.84 (m, 9H), m/z = 700.34.57-3.47 (m, 11H), 3.17-2.77 (m, 2H), 2.76-2.47 (m, 7H), 2.39- [M + H]⁺2.08 (m, 1H), 1.77-1.35 (m, 7H). I-42 ¹H NMR (400 MHz, CD₃OD) δ8.62-8.21 (m, 2H), 7.60-6.84 (m, 9H), m/z = 686.4 4.59-3.46 (m, 13H),3.25-2.88 (m, 2H), 2.78-2.45 (m, 8H), 2.36- [M + H]⁺ 2.01 (m, 1H),1.77-1.49 (m, 3H). I-43 ¹H NMR (400 MHz, CD₃OD) δ 8.44-8.12 (m, 1H),7.63-6.39 (m, m/z = 693.3 13H), 4.53-3.81 (m, 5H), 3.74-3.38 (m, 4H),3.22-2.81 (m, 2H), 2.77- [M + H]⁺ 1.96 (m, 8H), 1.83-1.42 (m, 4H),1.27-1.05 (m, 1H). I-44 ¹H NMR (400 MHz, CD₃OD) δ 8.92-8.39 (m, 2H),7.69-6.91 (m, 9H), m/z = 696.3 4.63-3.39 (m, 10H), 3.29-2.78 (m, 3H),2.73-2.59 (m, 5H), 2.54- [M + H]⁺ 2.05 (m, 3H), 1.86-1.52 (m, 4H),1.34-1.22 (m, 4H). I-45 ¹H NMR (400 MHz, CD₃OD) δ 7.97-6.87 (m, 12H),4.60-3.34 (m, m/z = 709.4 10H), 3.30-1.93 (m, 12H), 1.78-1.48 (m, 3H).[M + H]⁺ I-46 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.88 (m, 12H), 4.84-3.33(m, m/z = 730.4 9H), 3.29-1.89 (m, 12H), 1.85-1.55 (m, 3H), 1.45-1.30(m, 6H). [M + H]⁺ I-47 ¹H NMR (400 MHz, CD₃OD) δ 8.47-6.58 (m, 12H),4.77-4.16 (m, m/z = 707.3 2H), 4.16-3.34 (m, 9H), 3.27-2.47 (m, 8H),2.46-1.58 (m, 4H), 1.58- [M + H]⁺ 0.84 (m, 3H). I-48 ¹H NMR (400 MHz,CD₃OD) δ 7.87-6.77 (m, 13H), 4.67-3.37 (m, m/z = 708.4 11H), 3.28-2.28(m, 11H), 1.96-1.42 (m, 4H). [M + H]⁺ I-49 ¹H NMR (400 MHz, CD₃OD) δ8.10-6.86 (m, 13H), 4.53-4.26 (m, m/z = 684.3 1H), 4.13-3.93 (m, 2H),3.85-3.71 (m, 4H), 3.69-3.40 (m, 2H), 3.24- [M + H]⁺ 2.81 (m, 2H),2.76-2.42 (m, 7H), 2.03-1.25 (m, 7H). I-50 ¹H NMR (400 MHz, CD₃OD) δ7.65-6.90 (m, 14H), 4.60-3.40 (m, m/z = 654.3 6H), 3.25-2.80 (m, 3H),2.80-2.39 (m, 7H), 2.26-1.53 (m, 4H), 1.38- [M + H]⁺ 1.22 (m, 2H). I-51¹H NMR (400 MHz, CD₃OD) δ 7.70-6.79 (m, 9H), 4.60-3.47 (m, 6H), m/z =660.3 2.77-2.21 (m, 10H), 1.78-1.18 (m, 19H). [M + H]⁺ I-52 ¹H NMR (400MHz, CD₃OD) δ 7.65-6.97 (m, 13H), 4.57-3.39 (m, m/z = 710.3 6H),3.27-2.83 (m, 2H), 2.80-2.39 (m, 10H), 2.16-1.21 (m, 8H), [M + H]⁺0.96-0.85 (m, 6H). I-53 ¹H NMR (400 MHz, CD₃OD) δ 7.62-6.61 (m, 12H),4.73-3.37 (m, m/z = 695.3 9H), 3.25-2.97 (m, 4H), 2.77-2.36 (m, 8H),1.85-1.52 (m, 3H), 1.45- [M + H]⁺ 1.23 (m, 3H). I-54 ¹H NMR (400 MHz,CD₃OD) δ 8.20-6.66 (m, 12H), 4.59-3.82 (m, m/z = 767.4 7H), 3.75-3.33(m, 4H), 3.28-2.47 (m, 9H), 2.46-2.13 (m, 2H), 2.10- [M + H]⁺ 1.21 (m,6H), 1.16-0.76 (m, 4H). I-55 ¹H NMR (400 MHz, CD₃OD) δ 8.18-7.75 (m,2H), 7.39 (m, 2H), 7.25- m/z = 658.3 7.11 (m, 5H), 7.06 (m, 1H),4.60-3.64 (m, 8H), 3.55-3.44 (m, 2H), [M + H]⁺ 3.22-2.81 (m, 2H),2.77-2.57 (m, 7H), 2.37-1.99 (m, 1H), 1.86- 1.51 (m, 4H), 1.37-1.24 (m,3H). I-56 ¹H NMR (400 MHz, CD₃OD) δ 7.59-6.82 (m, 9H), 6.45-6.37 (m,1H), m/z = 658.3 4.65-3.64 (m, 7H), 3.63-3.41 (m, 2H), 3.15-2.50 (m,9H), 2.39- [M + H]⁺ 2.09 (m, 4H), 1.80-1.33 (m, 5H). I-57 ¹H NMR (400MHz, CD₃OD) δ 8.94-8.52 (m, 2H), 7.66-6.90 (m, m/z = 656.3 10H),4.62-3.35 (m, 8H), 3.26-2.18 (m, 10H), 1.77-1.28 (m, 5H). [M + H]⁺ I-58¹H NMR (400 MHz, CD₃OD) δ 8.53-6.87 (m, 12H), 4.61-4.21 (m, m/z = 683.32H), 4.20-3.74 (m, 3H), 3.73-3.37 (m, 4H), 3.22-2.93 (m, 1H), 2.85- [M +H]⁺ 2.55 (m, 10H), 1.78-1.33 (m, 6H), 1.28-1.15 (m, 2H). I-59 ¹H NMR(400 MHz, CD₃OD) δ 9.34-8.87 (m, 3H), 7.89-6.83 (m, m/z = 732.3 13H),4.58-3.42 (m, 8H), 3.28-2.01 (m, 11H), 1.90-1.37 (m, 4H). [M + H]⁺ I-60¹H NMR (400 MHz, CD₃OD) δ 8.85-6.67 (m, 11H), 4.64-3.37 (m, m/z = 670.410H), 3.21-2.34 (m, 13H), 1.74-1.44 (m, 3H). [M + H]⁺ I-61 ¹H NMR (400MHz, CD₃OD) δ 8.07-6.79 (m, 14H), 4.57-3.37 (m, m/z = 693.4 10H),3.26-2.83 (m, 2H), 2.76-2.01 (m, 8H), 1.75-1.45 (m, 3H). [M + H]⁺ I-62¹H NMR (400 MHz, CD₃OD) δ 8.13-6.67 (m, 12H), 4.59-4.01 (m, m/z = 695.32H), 3.98-3.41 (m, 4H), 3.26-2.31 (m, 10H), 2.23-1.97 (m, 1H), 1.80-[M + H]⁺ 1.49 (m, 3H), 1.40-1.03 (m, 4H). I-63 ¹H NMR (400 MHz, CD₃OD) δ8.87-8.73 (m, 1H), 8.59-8.49 (m, 1H), m/z = 731.5 8.14-8.02 (m, 1H),7.87-6.87 (m, 14H), 4.63-3.44 (m, 8H), 3.27- [M + H]⁺ 2.40 (m, 10H),2.38-2.19 (m, 1H), 2.01-1.40 (m, 4H). I-64 ¹H NMR (400 MHz, CD₃OD) δ9.23-8.95 (m, 1H), 8.74-8.39 (m, 1H), m/z = 695.3 7.97-6.84 (m, 11H),4.63-3.92 (m, 9H), 3.23-2.41 (m, 9H), 2.39- [M + H]⁺ 2.19 (m, 1H),2.12-1.41 (m, 4H). I-65 ¹H NMR (400 MHz, CD₃OD) δ 7.81-6.79 (m, 12H),4.62-3.36 (m, m/z = 709.3 8H), 3.27-2.38 (m, 10H), 2.32-2.11 (m, 1H),1.98-1.41 (m, 4H). [M + H]⁺ I-66 ¹H NMR (400 MHz, CD₃OD) δ 7.60-6.69 (m,12H), 4.55-3.84 (m, m/z = 777.4 8H), 3.71-3.36 (m, 3H), 3.13-2.88 (m,5H), 2.78-2.17 (m, 9H), 1.82- [M + H]⁺ 1.33 (m, 4H). I-67 ¹H NMR (400MHz, CD₃OD) δ 7.62-6.71 (m, 13H), 4.55-3.82 (m, m/z = 698.2 6H),3.72-3.37 (m, 3H), 3.29-2.38 (m, 11H), 2.38-1.96 (m, 1H), 1.79- [M + H]⁺1.33 (m, 7H). I-68 ¹H NMR (400 MHz, CD₃OD) δ 8.25-6.76 (m, 15H),4.65-3.40 (m, m/z = 737.3 9H), 3.28-2.78 (m, 2H), 2.76-2.49 (m, 7H),1.77-1.50 (m, 5H), 1.44- [M + H]⁺ 1.27 (m, 2H). I-69 ¹H NMR (400 MHz,CD₃OD) δ 8.46-6.53 (m, 12H), 4.60-3.82 (m, m/z = 781.4 8H), 3.68-3.44(m, 3H), 3.36-3.34 (m, 2H), 3.30-2.79 (m, 3H), 2.57- [M + H]⁺ 1.71 (m,13H), 0.96-0.20 (m, 5H). I-70 ¹H NMR (400 MHz, CD₃OD) δ 8.23-6.91 (m,15H), 4.65-3.37 (m, m/z = 737.4 9H), 3.12-1.36 (m, 15H). [M + H]⁺ I-71¹H NMR (400 MHz, CD₃OD) δ 7.62-6.67 (m, 15H), 4.57-4.12 (m, m/z = 734.42H), 4.12-3.35 (m, 10H), 3.21-2.41 (m, 9H), 1.79-1.46 (m, 4H). [M + H]⁺I-72 ¹H NMR (400 MHz, CD₃OD) δ 8.45-6.88 (m, 12H), 4.57-3.37 (m, m/z =711.4 7H), 3.27-1.93 (m, 11H), 1.86-1.11 (m, 5H). [M + H]⁺ I-73 ¹H NMR(400 MHz, CD₃OD) δ 7.65-6.88 (m, 12H), 4.58-3.36 (m, m/z = 725.4 10H),3.28-2.80 (m, 4H), 2.78-2.24 (m, 8H), 1.99-1.40 (m, 5H). [M + H]⁺ I-74¹H NMR (400 MHz, CD₃OD) δ 8.11-6.79 (m, 15H), 4.60-3.46 (m, m/z = 720.48H), 3.25-2.46 (m, 9H), 2.40-1.34 (m, 5H). [M + H]⁺ I-75 ¹H NMR (400MHz, CD₃OD) δ 7.59-6.88 (m, 12H), 4.62-3.41 (m, m/z = 711.3 8H),3.20-2.45 (m, 10H), 2.41-1.30 (m, 7H). [M + H]⁺ I-76 ¹H NMR (400 MHz,CD₃OD) δ 7.91-6.81 (m, 12H), 4.56-3.02 (m, m/z = 725.3 13H), 2.79-2.12(m, 10H), 1.63-1.35 (m, 8H). [M + H]⁺ I-77 ¹H NMR (400 MHz, CD₃OD) δ7.60-6.67 (m, 12H), 4.60-4.38 (m, m/z = 712.2 1H), 4.36-4.16 (m, 5H),4.07-3.81 (m, 2H), 3.73-3.34 (m, 3H), 3.29- [M + H]⁺ 2.36 (m, 11H),2.35-1.91 (m, 1H), 1.87-1.37 (m, 4H). I-78 ¹H NMR (400 MHz, CD₃OD) δ8.47-6.83 (m, 12H), 4.62-3.38 (m, m/z = 669.4 9H), 3.25-2.19 (m, 14H),1.81-1.41 (m, 4H). [M + H]⁺ I-79 ¹H NMR (400 MHz, CD₃OD) δ 9.00-8.49 (m,2H), 8.26-7.94 (m, 1H), m/z = 731.3 7.77-6.84 (m, 14H), 4.59-3.33 (m,8H), 3.28-2.76 (m, 3H), 2.75- [M + H]⁺ 2.23 (m, 8H), 2.22-1.97 (m, 1H),1.83-1.54 (m, 3H). I-80 ¹H NMR (400 MHz, CD₃OD) δ 9.08-8.85 (m, 1H),8.53-6.97 (m, m/z = 705.3 13H), 6.89-6.50 (m, 1H), 4.58-3.33 (m, 8H),3.28-2.74 (m, 3H), 2.73- [M + H]⁺ 2.55 (m, 5H), 2.54-2.21 (m, 2H),2.13-1.42 (m, 4H), 1.36-1.29 (m, 1H). I-81 ¹H NMR (400 MHz, CD₃OD) δ7.64-6.85 (m, 9H), 6.35-6.20 (m, 1H), m/z = 685.4 4.70-3.34 (m, 9H),3.27-2.79 (m, 2H), 2.74-2.54 (m, 6H), 2.35- [M + H]⁺ 1.96 (m, 2H),1.77-1.49 (m, 4H), 1.41-1.30 (m, 1H), 1.19-0.87 (m, 4H). I-82 ¹H NMR(400 MHz, CD₃OD) δ 7.68-6.68 (m, 12H), 4.62-3.44 (m, m/z = 768.4 11H),3.20-2.24 (m, 11H), 2.01-1.36 (m, 4H). [M + H]⁺ I-83 ¹H NMR (400 MHz,CD₃OD) δ 7.60-6.79 (m, 11H), 4.58-3.34 (m, m/z = 754.5 11H), 3.27-2.22(m, 12H), 2.05-1.15 (m, 11H). [M + H]⁺ I-84 ¹H NMR (400 MHz, CD₃OD) δ7.86-6.79 (m, 12H), 4.82-3.96 (m, m/z = 766.3 7H), 3.94-3.38 (m, 5H),3.28-2.32 (m, 9H), 2.29-1.61 (m, 4H), 1.60- [M + H]⁺ 1.23 (m, 8H). I-85¹H NMR (400 MHz, CD₃OD) δ 7.84-6.73 (m, 13H), 4.62-3.38 (m, m/z = 752.47H), 3.24-2.92 (m, 2H), 2.84-2.20 (m, 9H), 1.83-1.61 (m, 3H), 1.51- [M +H]⁺ 1.28 (m, 9H). I-86 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.80 (m, 12H),4.80-4.55 (m, m/z = 766.5 1H), 4.55-4.16 (m, 2H), 4.15-3.87 (m, 2H),3.84-3.43 (m, 3H), 3.41- [M + H]⁺ 3.35 (m, 3H), 3.27-3.11 (m, 1H),3.10-3.06 (m, 1H), 3.05-2.77 (m, 1H), 2.74-2.55 (m, 5H), 2.22-0.85 (m,14H). First eluting diastereomer purified by prep-HPLC on an Agilent 10Prep-C18 column (21.2 mm I.D. × 25 cm, 10 um), using H₂O/MeOH 0.1% TFAat a flow rate of 20 mL/min (wave length 214 nm). Rt = 10.5 min. I-87 ¹HNMR (400 MHz, CD₃OD) δ 7.63-6.87 (m, 12H), 4.80-4.60 (m, m/z = 766.51H), 4.55-3.36 (m, 11H), 3.27-2.96 (m, 2H), 2.89-2.42 (m, 8H), 1.87-[M + H]⁺ 1.44 (m, 10H), 1.39-1.26 (m, 1H). Second eluting diastereomerpurified by prep-HPLC on an Agilent 10 Prep-C18 column (21.2 mm I.D. ×25 cm, 10 um), using H₂O/MeOH 0.1% TFA at a flow rate of 20 mL/min (wavelength 214 nm). Rt = 12.7 min.

Synthesis ofN—((R)-1-benzylpiperidin-3-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-88

Step 1: ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylatehydrochloride

To a solution of the product of 2-(tert-butyl) 7-ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate(3.5 g, 7.14 mmol; see synthesis of I-1) in DCM (40 mL) was added asolution of HCl in dioxane (4M, 20 mL). The resulting mixture wasstirred for 3 h. The solvent was removed under vacuum to afford theproduct (3.0 g, quant.). LCMS m/z=390.2 [M+H]⁺.

Step 2: ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate

A mixture of ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylatehydrochloride (1.74 g, 4.1 mmol), 4-isopropoxy-3-methoxybenzoic acid(1.03 g, 4.92 mmol), EDCI (1.18 g, 6.15 mmol), HOBt (830 mg, 6.15 mmol)and DIEA (1.06 g, 8.2 mmol) in DMF (10 mL) was stirred overnight. Thereaction mixture was diluted with water and extracted with EtOAc threetimes. The combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (2.5% MeOH/DCM) to give the product (2.1 g, 88%)as a white solid. LCMS m/z=582.3 [M+H]⁺.

Step 3:5-(2-(6-chloro-M-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid

To a solution of ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate (2.1 g, 3.61 mmol) inMeOH (20 mL) was added an aqueous solution of NaOH (1M, 7.2 mL). Theresulting mixture was stirred for 3 h. The solvent was removed undervacuum and the residue obtained diluted with water. The pH was adjustedto ˜1 by addition of 1M HCl and the aqueous layer extracted with EtOActhree times. The combined organic layers were washed with water andbrine, dried over Na₂SO₄ and concentrated to afford the product (1.7 g,85% yield) as a white solid. LCMS m/z=554.2 [M+H]⁺.

Step 4:N—((R)-1-benzylpiperidin-3-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(I-88)

To a solution of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid (50 mg, 0.09 mmol) in DMA (1 mL) was added(R)-1-benzylpiperidin-3-amine (21 mg, 0.11 mmol), EDCI (26 mg, 0.14mmol), HOBt (18 mg, 0.14 mmol) and DIPEA (44 mg, 0.27 mmol). Theresulting mixture was stirred for 14 h. Water was added and the aqueouslayer was extracted with EtOAc three times. The combined organic layerswere washed with water and brine and dried over Na₂SO₄. The solvent wasremoved and the residue purified by prep-TLC (6% MeOH/DCM) to afford1-88 (30 mg, 46%) as a white solid. LCMS m/z=726.3 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ 7.59-6.69 (m, 12H), 4.75-4.30 (m, 2H), 3.92-3.46 (m, 12H),3.22-2.48 (m, 7H), 2.34-1.65 (m, 5H), 1.41-1.26 (m, 8H).

The compounds listed in Table 3 were synthesized using analogous methodsto those shown for 1-88, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers (or enantiomers where applicable) or separated bypreparative chiral HPLC as indicated.

Table 3. Compounds made by a method analogous to I-88 # ¹H NMRChromatography conditions, if applicable LCMS I-89 ¹H NMR (400 MHz,CD₃CD) δ 7.76-6.62 (m, 12H), 4.78-4.54 (m, m/z = 740.4 1H), 4.53-4.09(m, 2H), 4.08-3.75 (m, 6H), 3.73-3.37 (m, 4H), [M + H]⁺ 3.22-2.94 (m,3H), 2.79-2.27 (m, 4H), 2.24-1.81 (m, 2H), 1.80- 1.46 (m,, 3H),1.44-1.28 (m, 8H). I-90 ¹H NMR (400 MHz, CD₃OD) δ 7.74-6.63 (m, 12H),4.78-4.30 (m, m/z = 754.4 2H), 4.26-3.77 (m, 8H), 3.76-3.60 (m, 3H),3.58-3.37 (m, 3H), [M + H]⁺ 3.26-2.72 (m, 5H), 2.71-1.80 (m, 5H),1.78-1.49 (m, 2H), 1.41- 1.22 (m, 8H). I-91 ¹H NMR (400 MHz, CD₃OD) δ8.58-6.55 (m, 11H), 4.78-3.37 (m, m/z = 743.3 11H), 3.25-2.97 (m, 2H),2.91-2.26 (m, 8H), 2.24-1.98 (m, 1H), [M + H]⁺ 1.87-1.50 (m, 4H),1.47-1.27 (m, 10H). I-92 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.63 (m, 12H),4.76-3.73 (m, m/z = 758.3 12H), 3.72-3.57 (m, 1H), 3.50 (d, J = 6.4 Hz,1H), 3.40 (s, 1H), 3.29- [M + H]⁺ 2.98 (m, 2H), 2.88-2.42 (m, 6H),2.30-1.98 (m, 1H), 1.48-0.86 (m, 10H), 0.68 (d, J = 6.2 Hz, 1H). I-93 ¹HNMR (400 MHz, CD₃OD) δ 7.64-6.59 (m, 7H), 4.76-3.77 (m, m/z = 734.4 9H),3.74-3.37 (m, 3H), 3.25-2.42 (m, 8H), 2.38-1.46 (m, 10H), [M + H]⁺1.44-1.23 (m, 10H), 1.20-0.90 (m, 3H). I-94 ¹H NMR (400 MHz, CD₃OD) δ8.58-6.52 (m, 7H), 4.79-3.36 (m, m/z = 816.5 11H), 3.27-2.38 (m, 8H),2.37-1.44 (m, 8H), 1.44-1.08 (m, 13H), [M + H]⁺ 1.08-0.62 (m, 3H). I-95¹H NMR (400 MHz, CD₃OD) δ 7.71-6.57 (m, 7H), 4.76-3.34 (m, m/z = 722.411H), 3.27-2.88 (m, 2H), 2.88-2.70 (m, 2H), 2.69-1.95 (m, 4H), [M + H]⁺1.80-1.45 (m, 2H), 1.40-1.26 (m, 9H), 1.25-0.96 (m, 3H), 0.93- 0.84 (m,7H), 0.80-0.70 (m, 3H). I-96 ¹H NMR (400 MHz, CD₃OD) δ 7.69-6.60 (m,7H), 4.78-4.23 (m, m/z = 722.4 3H), 4.22-3.89 (m, 2H), 3.87-3.78 (m,3H), 3.76-3.33 (m, 3H), [M + H]⁺ 3.25-2.98 (m, 2H), 2.95-2.67 (m, 3H),2.67-1.98 (m, 4H), 1.82- 1.41 (m, 2H), 1.41-1.29 (m, 8H), 1.28-0.96 (m,4H), 0.93-0.84 (m, 6H), 0.81-0.70 (m, 3H). I-97 ¹H NMR (400 MHz, CD₃OD)δ 7.66-6.60 (m, 7H), 4.79-3.76 (m, m/z = 708.4 9H), 3.75-3.36 (m, 3H),3.28-2.44 (m, 8H), 2.41-1.93 (m, 1H), [M + H]⁺ 1.83-1.46 (m, 3H),1.43-1.26 (m, 9H), 1.20 (m, 2H), 1.04-0.84 (m, 5H), 0.84-0.69 (m, 2H).I-98 ¹H NMR (400 MHz, CD₃OD) δ 7.66-6.59 (m, 12H), 4.78-4.35 (m, m/z =742.3 2H), 4.33-3.96 (m, 2H), 3.95-3.38 (m, 8H), 3.26-2.75 (m, 5H), [M +H]⁺ 2.72-2.15 (m, 5H), 1.90-1.60 (m, 2H), 1.43-1.19 (m, 9H). I-99 ¹H NMR(400 MHz, CD₃OD) δ 7.73-6.49 (m, 12H), 4.67-3.78 (m, m/z = 728.3 9H),3.73-3.42 (m, 4H), 3.29-3.05 (m, 4H), 2.73-2.29 (m, 5H), [M + H]⁺2.11-1.66 (m, 3H), 1.41-1.30 (m, 6H). I-100 ¹H NMR (400 MHz, CD₃OD) δ7.70-6.46 (m, 12H), 4.74-3.78 (m, m/z = 742.3 9H), 3.74-3.34 (m, 5H),3.28-3.05 (m, 2H), 3.01-2.81 (m, 4H), [M + H]⁺ 2.68-2.44 (m, 4H),2.10-1.72 (m, 3H), 1.42-1.22 (m, 7H). First eluting diastereomerpurified by chiral prep-HPLC on a UniChiral CNZ-5H column (5 cm I.D. ×25 cm), using MeOH 0.1% DEA at a flow rate of 90 mL/min (wave length 254nm). Rt = 12.5 min I-101 ¹H NMR (400 MHz, CD₃OD) δ 7.68-6.47 (m, 12H),4.76-3.79 (m, m/z = 742.4 9H), 3.76-3.33 (m, 5H), 3.28-3.05 (m, 2H),3.01-2.81 (m, 4H), [M + H]⁺ 2.70-2.48 (m, 4H), 2.08-1.75 (m, 3H),1.42-1.24 (m, 7H). Second eluting diastereomer purified by chiralprep-HPLC on a UniChiral CNZ-5H column (5 cm I.D. × 25 cm), using MeOH0.1% DEA at a flow rate of 90 mL/min (wave length 254 nm). Rt = 13.9 minI-102 ¹H NMR (400 MHz, CD₃OD) δ 7.63-6.61 (m, 12H), 4.77-3.38 (m, m/z =758.4 17H), 3.27-1.94 (m, 10H), 1.40-1.33 (m, 3H), 1.24-1.05 (m, 3H),[M + H]⁺ 0.79-0.67 (m, 1H). I-103 ¹H NMR (400 MHz, CD₃OD) δ 7.65-6.60(m, 12H), 4.65 (m, 3H), m/z = 756.4 4.21-3.69 (m, 6H), 3.69-3.38 (m,4H), 3.26-3.15 (m, 1H), 3.12- [M + H]⁺ 2.74 (m, 5H), 2.69-2.50 (m, 4H),2.31-1.67 (m, 3H), 1.45-0.89 (m, 10H). I-104 ¹H NMR (400 MHz, CD₃OD) δ7.83-6.58 (m, 7H), 4.78-3.35 (m, m/z = 816.4 11H), 3.25-2.16 (m, 8H),2.12-1.44 (m, 8H), 1.43-0.71 (m, 16H). [M + H]⁺ I-105 ¹H NMR (400 MHz,CD₃OD) δ 7.67-6.57 (m, 12H), 4.78-3.34 (m, m/z = 758.4 15H), 3.28-1.92(m, 9H), 1.45-1.03 (m, 8H), 0.79-0.67 (m, 1H). [M + H]⁺ I-106 ¹H NMR(400 MHz, CD₃OD) δ 7.79-6.44 (m, 12H), 4.74-3.39 (m, m/z = 758.4 15H),3.29-2.98 (m, 2H), 2.87-2.42 (m, 5H), 2.31-1.96 (m, 1H), [M + H]⁺1.42-1.12 (m, 9H), 0.72-0.67 (m, 1H). I-107 ¹H NMR (400 MHz, CD₃OD) δ7.68-6.65 (m, 7H), 4.71-3.77 (m, m/z = 764.5 9H), 3.72-3.34 (m, 6H),3.28-2.94 (m 4H), 2.83-2.58 (m, 5H), [M + H]⁺ 2.32-1.96 (m, 1H),1.68-1.58 (m, 6H), 1.43-1.27 (m, 10H), 1.24- 1.04 (m, 5H), 0.93-0.83 (m,2H), 0.65-0.63 (m, 1H). I-108 ¹H NMR (400 MHz, CD₃OD) δ 7.81-6.44 (m,7H), 4.81-4.41 (m, m/z = 764.5 3H), 4.39-4.08 (m, 1H), 4.07-3.79 (m,5H), 3.73-3.52 (m, 2H), [M + H]⁺ 3.47-3.36 (m, 1H), 3.24-2.94 (m, 3H),2.80-2.61 (m, 4H), 2.57- 2.14 (m, 2H), 1.70-1.56 (m, 5H), 1.41-1.35 (m,9H), 1.23-1.05 (m, 5H), 0.92-0.81 (m, 4H). I-109 ¹H NMR (400 MHz, CD₃OD)δ 7.64-6.59 (m, 12H), 4.78-3.36 (m, m/z = 728.4 12H), 3.27-2.51 (m, 6H),2.48-1.96 (m, 2H), 1.84-1.55 (m, 3H), [M + H]⁺ 1.43-1.22 (m, 7H). I-110¹H NMR (400 MHz, CD₃OD) δ 7.63-6.57 (m, 12H), 4.77-3.73 (m, m/z = 753.48H), 3.70-2.86 (m, 9H), 2.83-2.29 (m, 6H), 1.42-1.16 (m, 6H). [M + H]⁺First eluting diastereomer purified by chiral prep-HPLC on a UniChiralCND-5H column (2.21 cm I.D. × 25 cm), using Hexane/EtOH (70/30) at aflow rate of 25 mL/min (wave length 254 nm). Rt = 9.1 min I-111 ¹H NMR(400 MHz, CD₃OD) δ 7.64-6.40 (m, 12H), 4.76-4.16 (m, m/z = 753.4 3H),4.02-3.34 (m, 9H), 3.28-2.22 (m, 10H), 1.41-1.24 (m, 7H). [M + H]⁺Second eluting diastereomer purified by chiral prep-HPLC on a UniChiralCND-5H column (2.21 cm I.D. × 25 cm), using Hexane/EtOH (70/30) at aflow rate of 25 mL/min (wave length 254 nm). Rt = 15.0 min I-112 ¹H NMR(400 MHz, CD₃OD) δ 7.64-6.62 (m, 7H), 4.79-3.77 (m, m/z = 748.4 9H),3.72-3.38 (m, 3H), 3.26-2.50 (m, 8H), 1.78-1.50 (m, 7H), [M + H]⁺1.43-0.74 (m, 17H). I-113 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.62 (m, 7H),4.80-3.77 (m, m/z = 748.4 9H), 3.73-3.39 (m, 3H), 3.25-2.18 (m, 8H),1.79-1.53 (m, 7H), [M + H]⁺ 1.45-0.72 (m, 17H). I-114 ¹H NMR (400 MHz,CD₃OD) δ 7.63-7.49 (m, 1H), 7.43-6.62 (m, m/z = 708.5 6H), 4.76-3.37 (m,12H), 3.26-2.17 (m, 10H), 1.80-1.45 (m, 3H), [M + H]⁺ 1.43-1.27 (m,10H), 1.07-0.68 (m, 7H). I-115 ¹H NMR (400 MHz, CD₃OD) δ 8.48-6.57 (m,11H), 4.77-3.36 (m, m/z = 758.4 12H), 3.26-2.96 (m, 2H), 2.90-2.40 (m,7H), 2.35-2.14 (m, 1H), [M + H]⁺ 2.03-1.46 (m, 3H), 1.43-1.15 (m, 7H).I-116 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.61 (m, 7H), 4.76-3.38 (m, m/z =764.5 14H), 3.25-2.85 (m, 2H), 2.81-2.39 (m, 6H), 2.11-1.83 (m, 2H),[M + H]⁺ 1.81-0.96 (m, 20H). I-117 ¹H NMR (400 MHz, CD₃OD) δ 7.63-6.63(m, 12H), 4.80-3.36 (m, m/z = 726.4 16H), 3.26-2.45 (m, 7H), 2.351.47(m, 4H)1.45-1.27 (m, 8H). [M + H]⁺ First eluting diastereomer purifiedby chiral prep-HPLC on a UniChiral CND-5H column (3 cm I.D. × 25 cm),using Hexane/EtOH (70/30) at a flow rate of 45 mL/min (wave length 254nm). Rt = 10.3 min I-118 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.69 (m, 12H),4.76-3.37 (m, m/z = 726.4 16H), 3.27-2.45 (m, 6H), 2.36-1.48 (m, 3H),1.44-1.26 (m, 8H). [M + H]⁺ Second eluting diastereomer purified bychiral prep-HPLC on a UniChiral CND-5H column (3 cm I.D. × 25 cm), usingHexane/EtOH (70/30) at a flow rate of 45 mL/min (wave length 254 nm). Rt= 13.8 min I-119 ¹H NMR (400 MHz, CD₃OD) δ 7.66-6.90 (m, 12H), 4.65-4.46(m, m/z = 685.3 1H), 4.14-3.80 (m, 6H), 3.73-3.37 (m, 2H), 3.26-2.79 (m,4H), [M + H]⁺ 2.76-2.22 (m, 4H), 2.22-1.62 (m, 1H), 1.57-1.37 (m, 4H),1.35- 1.28 (m, 9H). I-120 ¹H NMR (400 MHz, CD₃OD) δ 7.66-6.55 (m, 12H),4.78-3.38 (m, m/z = 714.3 11H), 3.17-2.81 (m, 4H), 2.75-2.48 (m, 5H),2.44-2.02 (m, 1H), [M + H]⁺ 1.41-1.30 (m, 8H). I-121 ¹H NMR (400 MHz,CD₃OD) δ 7.65-6.47 (m, 11H), 4.76-4.14 (m, m/z = 730.3 3H), 4.11-3.37(m, 8H), 3.27-2.38 (m, 10H), 2.27-1.61 (m, 1H), [M + H]⁺ 1.41-1.22 (m,6H). I-122 ¹H NMR (400 MHz, CD₃OD) δ 7.65-6.50 (m, 12H), 4.80-4.36 (m,m/z = 714.3 2H), 4.36-3.93 (m, 1H), 3.92-3.60 (m, 6H), 3.59-3.34 (m,2H), [M + H]⁺ 3.21-2.78 (m, 4H), 2.77-2.31 (m, 6H), 1.46-1.20 (m, 8H).I-123 ¹H NMR (400 MHz, CD₃OD) δ 7.64-6.41 (m, 11H), 4.69-3.77 (m, m/z =730.2 8H), 3.77-3.37 (m, 3H), 3.25-2.39 (m, 10H), 2.38-1.50 (m, 2H),[M + H]⁺ 1.43-1.22 (m, 8H). I-124 ¹H NMR (400 MHz, CD₃OD) δ 8.52-6.62(m, 7H), 4.74-3.75 (m, m/z = 638.3 8H), 3.74-3.37 (m, 3H), 3.28-2.76 (m,3H), 2.76-2.41 (m, 5H), [M + H]⁺ 2.38-1.71 (m, 1H), 1.42-1.09 (m, 11H).I-125 ¹H NMR (400 MHz, CD₃OD) δ 7.68-6.60 (m, 7H), 4.65-3.78 (m, m/z =638.3 8H), 3.73-3.35 (m, 3H), 3.25-2.88 (m, 2H), 2.84-2.17 (m, 6H), [M +H]⁺ 2.10-1.57 (m, 1H), 1.36-1.28 (m, 10H). I-126 ¹H NMR (400 MHz, CD₃OD)δ 8.55-6.50 (m, 11H), 4.78-4.00 (m, m/z = 743.3 4H), 3.99-3.77 (m, 5H),3.74-3.37 (m, 3H), 3.27-2.41 (m, 10H), [M + H]⁺ 1.87-1.54 (m, 3H),1.42-1.24 (m, 8H). I-127 ¹H NMR (400 MHz, CD₃OD) δ 7.59-6.55 (m, 11H),4.79-3.36 (m, m/z = 758.4 13H), 3.29-2.28 (m, 11H), 2.21-1.46 (m, 5H),1.42-1.30 (m, 7H). [M + H]⁺ I-128 ¹H NMR (400 MHz, CD₃OD) δ 7.72-6.42(m, 11H), 4.78-4.12 (m, m/z = 758.4 4H), 4.11-3.34 (m, 9H), 3.23-1.52(m, 14H), 1.37-1.26 (m, 7H). [M + H]⁺ I-129 ¹H NMR (400 MHz, CD₃OD) δ7.87-6.63 (m, 7H), 4.743.36 (m, m/z = 764.5 13H), 3.262.25 (m, 10H),1.770.62 (m, 21H). [M + H]⁺ I-130 ¹H NMR (400 MHz, CD₃OD) δ 7.66-6.61(m, 7H), 4.76-3.99 (m, m/z = 750.4 4H), 3.97-3.37 (m, 11H), 3.28-2.76(m, 3H), 2.75-1.65 (m, 7H), [M + H]⁺ 1.61-0.87 (m, 17H). I-131 ¹H NMR(400 MHz, CD₃OD) δ 7.66-6.61 (m, 7H), 4.76-3.99 (m, m/z = 750.4 4H),3.97-3.37 (m, 11H), 3.28-2.76 (m, 3H), 2.75-1.65 (m, 7H), [M + H]⁺1.61-0.87 (m, 17H) I-132 ¹H NMR (400 MHz, CD₃OD) δ 7.70-6.58 (m, 7H),4.79-3.77 (m, m/z = 734.4 9H), 3.76-3.35 (m, 3H), 3.30-2.98 (m, 2H),2.96-2.41 (m, 6H), [M + H]⁺ 1.86-1.45 (m, 9H), 1.42-1.26 (m, 9H),1.17-0.87 (m, 3H). I-133 ¹H NMR (400 MHz, CD₃OD) δ 7.71-6.60 (m, 11H),4.76-3.95 (m, m/z = 810.4 4H), 3.95-3.36 (m, 8H), 3.26-2.82 (m, 3H),2.82-1.56 (m, 12H), [M + H]⁺ 1.43-1.22 (m, 8H). I-134 ¹H NMR (400 MHz,CD₃OD) δ 7.74-6.59 (m, 11H), 4.78-3.35 (m, m/z = 810.4 12H), 3.24-2.37(m, 10H), 2.33-1.45 (m, 5H), 1.43-1.19 (m, 7H). [M + H]⁺ I-135 ¹H NMR(400 MHz, CD₃OD) δ 7.66-6.60 (m, 7H), 4.78-4.24 (m, m/z = 764.5 3H),3.90 (m, 2H), 3.86 (m, 1H), 3.82 (m, 3H), 3.75-3.35 (m, 4H), [M + H]⁺3.24-2.96 (m, 3H), 2.96-2.78 (m, 1H), 2.77-2.48 (m, 5H), 1.69 (m, 5H),1.51 (m, 1H), 1.43-1.28 (m, 7H), 1.27-1.05 (m, 5H), 1.03- 0.76 (m, 3H).I-136 ¹H NMR (400 MHz, CD₃OD) δ 7.72-6.04 (m, 12H), 4.75-3.98 (m, m/z =740.4 3H), 3.96-3.36 (m, 8H), 3.26-2.88 (m, 2H), 2.84-2.17 (m, 7H), [M +H]⁺ 1.41-1.22 (m, 6H). I-137 ¹H NMR (400 MHz, CD₃OD) δ 7.67-6.52 (m,12H), 4.76-3.92 (m, m/z = 738.3 4H), 3.91-3.36 (m, 8H), 3.28-2.85 (m,3H), 2.84-2.08 (m, 8H), [M + H]⁺ 1.42-1.19 (m, 7H). I-138 ¹H NMR (400MHz, CD₃OD) δ 8.77-8.51 (m, 2H), 8.00-6.65 (m, m/z = 743.4 9H),4.79-3.79 (m, 9H), 3.73-3.39 (m, 3H), 3.24-2.12 (m, 11H), [M + H]⁺1.92-1.57 (m, 3H), 1.45-1.23 (m, 7H). I-139 ¹H NMR (400 MHz, CD₃OD) δ7.70-6.63 (m, 10H), 4.76-3.34 (m, m/z = 783.4 12H), 3.26-2.86 (m, 4H),2.85-2.42 (m, 5H), 1.96-1.63 (m, 3H), [M + H]⁺ 1.46-1.14 (m, 9H). I-140¹H NMR (400 MHz, CD₃OD) δ 7.66-6.64 (m, 7H), 4.75-3.38 (m, m/z = 762.412H), 3.26-2.36 (m, 9H), 1.75-1.01 (m, 25H). [M + H]⁺ I-141 ¹H NMR (400MHz, CD₃OD) δ 7.72-6.58 (m, 7H), 4.80-3.36 (m, m/z = 762.4 13H),3.23-2.42 (m, 8H), 1.77-1.05 (m, 25H). [M + H]⁺ I-142 ¹H NMR (400 MHz,CD₃OD) δ 7.65-6.61 (m, 7H), 4.78-3.39 (m, m/z = 764.4 12H), 3.25-2.97(m, 2H), 2.85-2.52 (m, 5H), 2.08-1.08 (m, 24H). [M + H]⁺ I-143 ¹H NMR(400 MHz, CD₃OD) δ 7.90-6.59 (m, 10H), 4.72-3.37 (m, m/z = 783.5 13H),3.27-2.91 (m, 3H), 2.90-2.56 (m, 7H), 1.83-1.61 (m, 3H), [M + H]⁺1.44-1.33 (m, 6H), 1.22-1.18 (m, 2H). I-144 ¹H NMR (400 MHz, CD₃OD) δ7.68-6.57 (m, 11H), 4.75-3.79 (m, m/z = 760.4 9H), 3.73-3.41 (m, 3H),3.28-2.79 (m, 3H), 2.78-2.54 (m, 6H), [M + H]⁺ 2.44-2.00 (m, 2H),1.73-1.50 (m, 3H), 1.41-1.29 (m, 8H). I-145 ¹H NMR (400 MHz, CD₃OD) δ7.52-6.55 (m, 12H), 4.77-4.52 (m, m/z = 758.4 3H), 4.52-4.30 (m, 2H),4.11-4.93 (m, 1H), 4.92-3.79 (m, 5H), [M + H]⁺ 3.75-3.56 (m, 2H),3.55-3.35 (m, 2H), 3.27-3.02 (m, 2H), 2.85- 2.72 (m, 3H), 2.65-2.23 (m,4H), 1.45-1.28 (m, 7H), 1.23-0.84 (m, 3H). First eluting diastereomerpurified by chiral prep-HPLC on a CHIRALPAK IF column (0.46 cm I.D. × 15cm), using n- Hexane/EtOH 0.1% DEA (60/40) at a flow rate of 1.0 mL/min(wave length 210 nm). Rt = 8.2 min I-146 ¹H NMR (400 MHz, CD₃OD) δ7.55-6.60 (m, 12H), 4.66-4.12 (m, m/z = 758.3 6H), 4.05-3.75 (m, 6H),3.70-3.58 (m, 1H), 3.52-3.35 (m, 3H), [M + H]⁺ 3.26-3.01 (m, 2H),2.84-2.47 (m, 6H), 1.40-1.97 (m, 9H), 1.46- 1.35 (m, 9H), 0.71-0.66 (m,2H). Second eluting diastereomer purified by chiral prep-HPLC on aCHIRALPAK IF column (0.46 cm I.D. × 15 cm), using n- Hexane/EtOH 0.1%DEA (60/40) at a flow rate of 1.0 mL/min (wave length 210 nm). Rt = 10.5min I-147 ¹H NMR (400 MHz, CD₃OD) δ 8.07-6.76 (m, 12H), 4.80-3.98 (m,m/z = 758.4 6H), 3.97-3.58 (m, 7H), 3.55-3.33 (m, 2H), 3.29-1.63 (m,8H), [M + H]⁺ 1.37-0.88 (m, 9H). First eluting diastereomer purified byprep-HPLC on an Agilent 10 Prep-C18 column (21.2 mm I.D. × 25 cm, 10um), using H₂O/ACN 0.1% TFA at a flow rate of 20 mL/min (wave length 214nm). Rt = 12.9 min I-148 ¹H NMR (400 MHz, CD₃OD) δ7.62-6.88 (m, 12H),4.67-4.23 (m, m/z = 758.4 5H), 4.13-3.68 (m, 8H), 3.63-3.33 (m, 2H),3.28-2.58 (m, 5H), [M + H]⁺ 2.54-2.13 (m, 3H), 1.38-1.27 (m, 6H),1.23-1.06 (m, 3H). Second eluting diastereomer purified by prep-HPLC onan Agilent 10 Prep-C18 column (21.2 mm I.D. × 25 cm, 10 um), usingH₂O/ACN 0.1% TFA at a flow rate of 20 mL/min (wave length 214 nm). Rt =13.9 min I-149 ¹H NMR (400 MHz, CD₃OD) δ 7.92-6.63 (m, 14H), 4.80-3.45(m, m/z = 752.5 11H), 3.27-2.07 (m, 8H), 1.77-1.18 (m, 11H) 1H),1.80-1.52 (m, [M + H]⁺ 2H), 1.48-0.86 (m, 9H). I-150 ¹H NMR (400 MHz,CD₃OD) δ 8.58-6.67 (m, 16H), 4.79-3.39 (m, m/z = 762.4 12H), 3.23-1.96(m, 9H), 1.88-1.33 (m, 9H). [M + H]⁺ I-151 ¹H NMR (400 MHz, CD₃OD) δ8.78-8.71 (m, 1H), 8.70-8.61 (m, m/z = 763.4 0.5H), 8.40-8.29 (m, 0.5H),7.61-6.65 (m, 13H), 4.79-3.75 (m, [M + H]⁺ 8H), 3.70-3.35 (m, 3H),3.29-2.94 (m, 2H), 2.84-2.39 (m, 5H), 2.22-2.00 (m, 1H), 1.87-1.49 (m,3H), 1.42-1.31 (m, 5H), 1.29- 1.23 (m, 3H). I-152 ¹H NMR (400 MHz,CD₃OD) δ 7.68-6.41 (m, 11H), 4.77-4.13 (m, m/z = 758.4 3H), 4.11-3.33(m, 9H), 3.28-1.51 (m, 14H), 1.44-1.21 (m, 7H). [M + H]⁺ First elutingdiastereomer purified by chiral prep-HPLC on a UniChiral CND-5H column(21.2 mm I.D. × 250 mm), using ACN/IPA/DEA = 95/5/0.1, at a flow rate of20 mL/min (wave length 254 nm). Rt = 5.7 min. I-153 ¹H NMR (400 MHz,CD₃OD) δ 7.63-6.50 (m, 11H), 4.77-3.38 (m, m/z = 758.4 13H), 3.27-2.28(m, 10H), 2.20-1.47 (m, 4H), 1.42-1.27 (m, 6H). [M + H]⁺ Second elutingdiastereomer purified by chiral prep-HPLC on a UniChiral CND-5H column(21.2 mm I.D. × 250 mm), using ACN/IPA/DEA = 95/5/0.1, at a flow rate of20 mL/min (wave length 254 nm). Rt = 6.3 min. I-261 ¹H NMR (400 MHz,CD₃OD) δ 7.64-6.55 (m, 9H), 4.79-3.37 (m, m/z = 659.4 13H), 3.28-2.52(m, 8H), 2.38-1.78 (m, 1H), 1.44-1.25 (m, 6H). [M + H]⁺ First elutingenantiomer purified by chiral prep-HPLC on a UniChiral CND-5H column(21.2 mm I.D. × 250 mm), using n- Hexane/EtOH = 70/30, at a flow rate of20 mL/min (wave length 254 nm). Rt = 14.9 min. I-262 ¹H NMR (400 MHz,CD₃OD) δ 7.64-6.54 (m, 9H), 4.74-3.39 (m, m/z = 659.4 13H), 3.27-2.47(m, 8H), 2.43-1.93 (m, 1H), 1.42-1.28 (m, 6H). [M + H]⁺ Second elutingenantiomer purified by chiral prep-HPLC on a UniChiral CND-5H column(21.2 mm I.D. × 250 mm), using n- Hexane/EtOH = 70/30, at a flow rate of20 mL/min (wave length 254 nm). Rt = 17.9 min.

Synthesis of2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)-5-(2-phenylacetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-154

Step 1: 5-benzyl 2-(tert-butyl) 7-ethylhexahydro-2H-pyrrolo[3,4-c]pyridine-2,5,7(3H)-tricarboxylate

To a solution of Int-1 (5 g, 16.7 mmol) in DCM (50 mL) was added Et₃N(3.4 g, 33.5 mmol). After stirring for 30 min, CbzCl (3.1 g, 18.4 mmol)was added and stirring continued for 4 h. The reaction was quenched withwater and extracted with EtOAc three times. The combined organic layerswere washed with water, brine, and dried over Na₂SO₄. The solvent wasremoved in vacuo and the residue purified by column chromatography (20%EtOAc/PE) to afford the product (5.7 g, 79%) as a white solid. LCMSm/z=333.3 [M−Boc+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.26 (m, 5H), 5.13(d, J=3.9 Hz, 2H), 4.31-3.47 (m, 4H), 3.46-3.32 (m, 3H), 3.30 (d, J=1.6Hz, 1H), 3.24-1.58 (m, 5H), 1.46 (s, 9H), 1.29-1.23 (m, 3H).

Step 2:5-((benzyloxy)carbonyl)-2-(tert-butoxycarbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid

To a solution of 5-benzyl 2-(tert-butyl) 7-ethylhexahydro-2H-pyrrolo[3,4-c]pyridine-2,5,7(3H)-tricarboxylate (5.7 g,13.2 mmol) in MeOH (60 mL) was added aqueous NaOH (1M, 20 mL). Themixture was stirred at room temperature for 3 h, then diluted with waterand the pH adjusted to ˜3 by addition of 1M HCl. The aqueous layer wasextracted with EtOAc three times. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. Concentration affordedthe product (4.7 g, 88%) as a white solid. LCMS m/z=305.3 [M−Boc+H]⁺.

Step 3: 5-benzyl 2-(tert-butyl)7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)hexahydro-2H-pyrrolo[3,4-c]pyridine-2,5(3H)-dicarboxylate

To a solution of5-((benzyloxy)carbonyl)-2-(tert-butoxycarbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid (4.5 g, 11.1 mmol) in DMA (50 mL) was added(S)-2-amino-N-methyl-5-phenylpentanamide (3.4 g, 16.7 mmol), EDCI (3.2g, 16.7 mmol), HOBt (1.7 g, 12.2 mmol) and DIEA (2.9 g, 22.3 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction was quenched with water and extracted with EtOAc three times.The combined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed and the residue purified by columnchromatography (5% MeOH/DCM) to afford the product (5.3 g, 80%) as awhite solid. LCMS m/z=493.4 [M−Boc+H]⁺.

Step 4: benzyl7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylatehydrochloride

To a solution of 5-benzyl 2-(tert-butyl)7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)hexahydro-2H-pyrrolo[3,4-c]pyridine-2,5(3H)-dicarboxylate(5.3 g, 8.9 mmol) in DCM (25 mL) was added a solution of HCl in dioxane(4M, 25 mL). The resulting mixture was stirred at room temperature for 1h. The solvent was removed to afford the product (7.8 g, quant.). LCMSm/z=493.4 [M+H]⁺.

Step 5: benzyl2-(4-isopropoxy-3-methoxybenzoyl)-7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate

A mixture of benzyl7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylatehydrochloride (5.1 g, 9.8 mmol), 4-isopropoxy-3-methoxybenzoic acid(2.47 g, 11.7 mmol), EDCI (2.8 g, 14.7 mmol), HOBt (2.0 g, 14.7 mmol)and DIEA (3.87 g, 30 mmol) in DMF (20 mL) was stirred overnight. Thereaction mixture was diluted with water and extracted with EtOAc threetimes. The combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (5% MeOH/DCM) to give the product (6.7 g, quant.)as a colorless oil. LCMS m/z=685.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ7.46-6.78 (m, 13H), 5.49 (s, 1H), 5.14 (d, J=2.7 Hz, 2H), 4.67-4.47 (m,1H), 4.34-4.11 (m, 2H), 3.83 (d, J=7.0 Hz, 4H), 3.59 (d, J=3.7 Hz, 2H),3.46-3.34 (m, 1H), 2.98 (d, J=53.8 Hz, 1H), 2.76-2.46 (m, 7H), 2.40 (t,J=7.3 Hz, 1H), 1.62 (d, J=33.2 Hz, 3H), 1.39-1.21 (m, 8H).

Step 6:2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

To a solution of benzyl2-(4-isopropoxy-3-methoxybenzoyl)-7-(((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)carbamoyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate(6.7 g, 9.8 mmol) in MeOH (70 mL) was added Pd/C (10%, 600 mg). Theresulting mixture was stirred under H₂ at room temperature overnight.The solution was filtered through celite and the filtrate concentratedto afford the product (5.2 g, 97%). LCMS m/z=551.4 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ 7.29-6.81 (m, 8H), 4.74-4.48 (m, 1H), 4.37-4.15 (m, 1H),3.90-3.81 (m, 3H), 3.78-3.35 (m, 4H), 3.06-2.82 (m, 3H), 2.78-2.16 (m,9H), 1.89-1.38 (m, 4H), 1.34-1.24 (m, 6H).

Step 7:2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)-5-(2-phenylacetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(I-154)

A mixture of2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(55 mg, 0.1 mmol), 2-phenylacetic acid (16 mg, 0.12 mmol), EDCI (23 mg,0.12 mmol), HOBt (20 mg, 0.15 mmol) and DIEA (32 mg, 0.25 mmol) in DMA(1.0 mL) was stirred at room temperature overnight. The reaction mixturewas diluted with water and extracted with EtOAc three times. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by prep-HPLCto afford 1-154 (24.2 mg, 37%) as a white solid. LCMS m/z=669.4 [M+H]⁺;¹H NMR (400 MHz, CD₃OD) δ 7.43-6.79 (m, 13H), 4.69-3.76 (m, 9H),3.74-3.34 (m, 3H), 3.28-2.87 (m, 2H), 2.87-2.49 (m, 6H), 2.48-2.17 (m,2H), 2.03-1.48 (m, 4H), 1.40-1.26 (m, 7H).

The compounds listed in Table 4 were synthesized using analogous methodsto those shown for 1-154, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers or separated by preparative HPLC or preparative TLC asindicated.

TABLE 4 Compounds made by a method analogous to I-154 # ¹H NMRChromatography conditions, if applicable LCMS I-155 ¹H NMR (400 MHz,CD₃OD) δ 8.61-8.24 (m, 1H), 7.87-7.63 m/z = 670.4 (m, 1H), 7.48-6.68 (m,10H), 4.84-3.35 (m, 11H), 3.29-2.10 [M + H]⁺ (m, 11H), 2.08-1.43 (m,4H), 1.40-1.22 (m, 8H). I-156 ¹H NMR (400 MHz, CD₃OD) δ 7.65-6.71 (m,12H), 4.77-3.78 m/z = 743.4 (m, 10H), 3.76-3.34 (m, 6H), 3.28-2.48 (m,6H), 2.37-1.47 [M + H]⁺ (m, 3H), 1.45-1.24 (m, 8H). I-157 ¹H NMR (400MHz, CD₃OD) δ 7.08-6.93 (m, 1H), 6.86-6.30 m/z = 722.5 (m, 12H),4.15-3.28 (m, 6H), 3.26-2.85 (m, 3H), 2.79-2.38 [M + H]⁺ (m, 5H),2.35-1.81 (m, 10H), 1.32-0.95 (m, 3H), 0.84-0.71 (m, 7H). I-158 ¹H NMR(400 MHz, CD₃OD) δ 8.99-8.84 (m, 1H), 8.53-8.33 m/z = 706.5 (m, 1H),8.20-7.89 (m, 2H), 7.88-7.53 (m, 2H), 7.29-6.72 [M + H]⁺ (m, 8H),4.74-4.31 (m, 2H), 4.31-3.98 (m, 1H), 3.88-3.35 (m, 9H), 2.84-2.17 (m,8H), 2.05-0.98 (m, 12H). I-159 ¹H NMR (400 MHz, CD₃OD) δ 7.75-6.81 (m,13H), 4.65-3.81 m/z = 708.5 (m, 8H), 3.80-3.33 (m, 7H), 2.82-2.38 (m,8H), 1.75-1.49 [M + H]⁺ (m, 3H), 1.37-1.27 (m, 8H). I-160 ¹H NMR (400MHz, CD₃OD) δ 9.34-9.11 (m, 1H), 8.20-7.72 m/z = 706.4 (m, 5H),7.29-6.79 (m, 8H), 4.72-3.80 (m, 7H), 3.78-3.34 [M + H]⁺ (m, 5H),2.89-2.28 (m, 8H), 2.08-1.55 (m, 3H), 1.37-1.26 (m, 8H). I-161 ¹H NMR(400 MHz, CD₃OD) δ 7.56-7.55 (m, 1H), 7.30-7.01 m/z = 708.5 (m, 12H),6.49-6.41 (m, 1H), 5.34-4.92 (m, 2H), 4.73-3.35 [M + H]⁺ (m, 11H),3.23-2.90 (m, 2H), 2.80-1.97 (m, 8H), 1.78-1.53 (m, 4H), 1.40-1.27 (m,8H). I-162 ¹H NMR (400 MHz, CD₃OD) δ 7.42-6.64 (m, 12H), 4.67-4.05 m/z =708.4 (m, 4H), 3.88-3.34 (m, 8H), 2.79-2.47 (m, 7H), 2.43-1.95 [M + H]⁺(m, 4H), 1.82-1.35 (m, 4H), 1.35-1.20 (m, 9H). I-163 ¹H NMR (400 MHz,CD₃OD) δ 8.57-6.81 (m, 10H), 4.70-3.35 m/z = 687.4 (m, 15H), 3.23-2.36(m, 9H), 1.85-1.22 (m, 11H). [M + H]⁺ I-164 ¹H NMR (400 MHz, CD₃OD) δ8.56-8.28 (m, 1H), 7.81-7.66 m/z = 684.4 (m, 1H), 7.41-6.83 (m, 10H),4.66-3.82 (m, 7H), 3.79-3.33 [M + H]⁺ (m, 4H), 3.28-2.78 (m, 6H),2.76-2.36 (m, 8H), 1.74-1.54 (m, 3H), 1.35-1.27 (m, 8H). I-165 ¹H NMR(400 MHz, CD₃OD) δ 8.99-8.84 (m, 2H), 8.25-8.07 m/z = 707.4 (m, 2H),7.93-7.75 (m, 1H), 7.27-7.02 (m, 7H), 7.02-6.83 [M + H]⁺ (m, 1H),4.69-3.78 (m, 8H), 3.70-3.37 (m, 5H), 2.83-2.49 (m, 7H), 1.85-1.50 (m,3H), 1.36-1.28 (m, 8H). I-166 ¹H NMR (400 MHz, CD₃OD) δ 8.28-8.17 (m,1H), 7.29-6.80 m/z = 660.4 (m, 8H), 4.66-4.19 (m, 3H), 3.90-3.77 (m,3H), 3.75-3.34 [M + H]⁺ (m, 4H), 3.29-3.08 (m, 1H), 3.06-1.95 (m, 12H),1.86-1.50 (m, 3H), 1.38-1.19 (m, 7H). I-167 ¹H NMR (400 MHz, CD₃OD) δ8.82-8.81 (m, 1H), 8.35-8.25 m/z = 720.5 (m, 1H), 8.04-7.97 (m, 1H),7.84-7.73 (m, 2H), 7.53-7.52 [M + H]⁺ (m, 1H), 7.23-6.83 (m, 8H),4.70-3.36 (m, 12H), 3.26-3.13 (m, 2H), 2.78-2.20 (m, 8H), 1.68-1.57 (m,3H), 1.34-1.26 (m, 9H). I-168 ¹H NMR (400 MHz, CD₃OD) δ 7.81-6.76 (m,14H), 4.69-3.72 m/z = 721.5 (m, 7H), 3.66-3.33 (m, 4H), 3.22-2.59 (m,7H), 2.51-1.99 [M + H]⁺ (m, 2H), 1.79-1.52 (m, 3H), 1.35-1.27 (m, 8H).I-169 ¹H NMR (400 MHz, CD₃OD) δ 7.26-6.85 (m, 8H), 4.63-4.51 m/z = 677.5(m, 1H), 4.34-4.32 (m, 1H), 4.22-4.15 (m, 1H), 3.84-3.34 [M + H]⁺ (m,12H), 3.25-3.12 (m, 1H), 2.74-2.61 (m, 7H), 2.44-2.33 (m, 1H), 2.11-2.08(m, 1H), 2.08-2.04 (m, 1H), 1.71-1.50 (m, 5H), 1.40-1.21 (m, 12H). I-170¹H NMR (400 MHz, CD₃OD) δ 7.56-7.55 (m, 1H), 7.30-7.01 m/z = 708.4 (m,12H), 6.49-6.41 (m, 1H), 5.23-4.85 (m, 2H), 4.67-4.52 [M + H]⁺ (m, 1H),4.36-4.22 (m, 1H), 4.20-3.97 (m, 1H), 3.88-3.82 (m, 3H), 3.78-3.71 (m,1H), 3.62-3.36 (m, 4H), 3.23-2.90 (m, 2H), 2.73-2.57 (m, 6H), 2.45-2.36(m, 1H), 2.20-2.00 (m, 1H), 1.78-1.40 (m, 4H), 1.36-1.27 (m, 8H). I-171¹H NMR (400 MHz, CD₃OD) δ 7.30-6.71 (m, 9H), 6.04-5.93 m/z = 658.5 (m,1H), 4.69-4.47 (m, 1H), 4.38-3.79 (m, 6H), 3.77-3.33 [M + H]⁺ (m, 4H),3.30-3.08 (m, 2H), 2.78-2.37 (m, 8H), 2.20-2.04 (m, 3H), 1.83-1.53 (m,3H), 1.39-1.22 (m, 7H). I-172 ¹H NMR (400 MHz, CD₃OD) δ 8.04-6.81 (m,12H), 4.67-4.02 m/z = 728.4 (m, 4H), 3.91-3.67 (m, 4H), 3.66-3.34 (m,4H), 3.22-2.70 [M + H]⁺ (m, 3H), 2.70-2.46 (m, 5H), 2.45-1.92 (m, 1H),1.85-1.50 (m, 3H), 1.50-1.12 (m, 9H). I-173 ¹H NMR (400 MHz, CD₃OD) δ9.63-8.23 (m, 12H), 6.22-5.57 m/z = 726.5 (m, 4H), 5.49-5.31 (m, 4H),5.31-4.90 (m, 5H), 4.36-3.91 [M + H]⁺ (m, 9H), 3.47-2.99 (m, 3H),2.96-2.69 (m, 10H). I-174 ¹H NMR (400 MHz, CD₃OD) δ 7.64-7.50 (m, 1H),7.34-6.82 m/z = 726.5 (m, 12H), 6.52-6.40 (m, 1H), 5.40-4.97 (m, 2H),4.75-3.34 [M + H]⁺ (m, 11H), 3.27-2.90 (m, 2H), 2.81-1.97 (m, 8H),1.86-1.43 (m, 4H), 1.40-1.25 (m, 8H). I-175 ¹H NMR (400 MHz, CD₃OD) δ7.53-6.67 (m, 12H), 4.72-4.24 m/z = 722.4 (m, 2H), 4.23-3.60 (m, 7H),3.60-3.34 (m, 2H), 3.28-2.79 [M + H]⁺ (m, 2H), 2.78-2.48 (m, 9H),2.48-1.92 (m, 2H), 1.86-1.43 (m, 3H), 1.40-1.18 (m, 10H). I-176 ¹H NMR(400 MHz, CD₃OD) δ 7.24-6.82 (m, 11H), 6.49-6.38 m/z = 738.5 (m, 1H),4.70-4.51 (m, 2H), 4.33-3.99 (m, 4H), 3.96-3.90 [M + H]⁺ (m, 1H),3.86-3.76 (m, 5H), 3.68-3.50 (m, 3H), 3.25-2.84 (m, 2H), 2.71-2.38 (m,8H), 2.03-1.63 (m, 3H), 1.38-1.25 (m, 9H). I-177 ¹H NMR (400 MHz, CD₃OD)δ 7.59-6.73 (m, 13H), 4.84-3.94 m/z = 736.5 (m, 3H), 3.94-3.80 (m, 3H),3.81-3.36 (m, 2H), 3.25-2.77 [M + H]⁺ (m, 2H), 2.77-2.46 (m, 6H),2.46-1.93 (m, 2H), 1.84-1.53 (m, 9H), 1.50-1.04 (m, 10H). I-178 ¹H NMR(400 MHz, CD₃OD) δ 7.43-6.72 (m, 13H), 4.76-4.18 m/z = 708.4 (m, 3H),4.16-3.73 (m, 7H), 3.61-3.38 (m, 2H), 3.13-2.90 [M + H]⁺ (m, 2H),2.77-2.37 (m, 8H), 1.77-1.24 (m, 11H). I-179 ¹H NMR (400 MHz, CD₃OD) δ8.25-6.67 (m, 12H), 4.76-4.30 m/z = 709.4 (m, 2H), 4.30-3.35 (m, 10H),3.28-2.93 (m, 2H), 2.80-2.15 [M + H]⁺ (m, 8H), 1.90-1.21 (m, 11H). I-180¹H NMR (400 MHz, CD₃OD) δ 7.63-6.30 (m, 12H), 4.77-3.80 m/z = 694.5 (m,6H), 3.79-3.32 (m, 5H), 3.27-2.35 (m, 9H), 2.32-1.48 [M + H]⁺ (m, 3H),1.47-1.17 (m, 8H). I-181 ¹H NMR (400 MHz, CD₃OD) δ 9.02-6.80 (m, 14H),4.75-3.99 m/z = 706.5 (m, 3H), 3.89-3.82 (m, 3H), 3.81-3.36 (m, 6H),2.88-2.25 [M + H]⁺ (m, 8H), 2.08-1.39 (m, 3H), 1.36-1.14 (m, 8H). I-182¹H NMR (400 MHz, CD₃OD) δ 8.15-6.69 (m, 12H), 4.73-4.08 m/z = 695.4 (m,3H), 3.92-3.40 (m, 8H), 3.01-2.32 (m, 8H), 2.09-1.19 [M + H]⁺ (m, 12H).I-183 ¹H NMR (400 MHz, CD₃OD) δ 7.28-6.28 (m, 9H), 4.71-4.16 m/z = 659.5(m, 3H), 3.89-3.71 (m, 4H), 3.663.53 (m, 2H), 2.82-2.49 (m, [M + H]⁺8H), 2.44-2.24 (m, 4H), 1.81-1.50 (m, 3H), 1.34-1.24 (m, 10H). I-184 ¹HNMR (400 MHz, CD₃OD) δ 8.66-6.81 (m, 11H), 4.72-3.96 m/z = 670.5 (m,3H), 3.95-3.35 (m, 9H), 3.28-2.58 (m, 7H), 2.57-1.99 [M + H]⁺ (m, 5H),1.95-1.51 (m, 3H), 1.50-1.16 (m, 8H). I-185 ¹H NMR (400 MHz, CD₃OD) δ7.28-6.83 (m, 8H), 4.72-3.35 m/z = 690.4 (m, 12H), 2.94-2.25 (m, 14H),1.77-1.52 (m, 3H), 1.35-1.24 [M + H]⁺ (m, 8H). I-186 ¹H NMR (400 MHz,CD₃OD) δ 7.31-6.75 (m, 8H), 4.75-4.11 m/z = 661.4 (m, 5H), 4.10-3.67 (m,5H), 3.67-3.33 (m, 3H), 3.29-2.77 [M + H]⁺ (m, 2H), 2.77-2.21 (m, 8H),2.18-1.60 (m, 3H), 1.58-1.27 (m, 7H). I-187 ¹H NMR (400 MHz, CD₃OD) δ8.30-6.72 (m, 9H), 4.68-3.36 m/z = 660.4 (m, 12H), 2.84-2.24 (m, 11H),1.87-1.20 (m, 11H). [M + H]⁺ I-188 ¹H NMR (400 MHz, CD3OD) δ 7.28-6.83(m, 8H), 4.72-3.35 m/z = 674.5 (m, 12H), 2.94-2.25 (m, 14H), 1.77-1.52(m, 3H), 1.35-1.24 [M + H]⁺ (m, 8H). I-189 ¹H NMR (400 MHz, CD₃OD) δ7.27-5.78 (m, 10H), 4.69-4.19 m/z = 658.5 (m, 4H), 3.91-3.35 (m, 8H),2.75-2.21 (m, 11H), 1.76-1.49 [M + H]⁺ (m, 3H), 1.34-1.24 (m, 8H). I-1901H NMR (400 MHz, CD₃OD) δ 7.78-6.81 (m, 12H), 4.63- m/z = 712.4 4.11 (m,4H), 3.86-3.77 (m, 3H), 3.72-3.37 (m, 4H), 2.79- [M + H]⁺ 2.36 (m, 7H),1.93-1.42 (m, 4H), 1.40-1.20 (m, 10H). I-191 ¹H NMR (400 MHz, CD₃OD) δ7.74-6.77 (m, 12H), 4.65-4.07 m/z = 708.5 (m, 4H), 3.99-3.33 (m, 8H),2.80-2.35 (m, 11H), 1.92-1.43 [M + H]⁺ (m, 3H), 1.41-1.08 (m, 8H). I-192¹H NMR (400 MHz, CD₃OD) δ 8.79-8.67 (m, 1H), 8.60-8.45 m/z = 698.5 (m,1H), 8.06-7.85 (m, 2H), 7.29-6.81 (m, 9H), 4.68-3.75 [M + H]⁺ (m, 7H),3.73-3.34 (m, 3H), 3.27-2.83 (m, 4H), 2.78-2.40 (m, 11H), 2.38-1.91 (m,2H), 1.88-1.47 (m, 3H), 1.45-1.29 (m, 6H). I-193 ¹H NMR (400 MHz, CD₃OD)δ 8.10-7.70 (m, 1H), 7.29-6.80 m/z = 660.4 (m, 8H), 4.74-4.16 (m, 4H),3.88-3.79 (m, 3H), 3.71-3.34 [M + H]⁺ (m, 4H), 3.28-2.83 (m, 1H),2.81-2.34 (m, 11H), 1.86-1.37 (m, 4H), 1.35-1.20 (m, 7H). I-194 ¹H NMR(400 MHz, CD₃OD) δ 9.13-8.88 (m, 1H), 8.54-8.34 m/z = 696.4 (m, 2H),7.96-7.88 (m, 1H), 7.25-6.92 (m, 8H), 4.73-4.16 [M + H]⁺ (m, 3H),3.79-3.33 (m, 8H), 2.88-2.42 (m, 8H), 1.84-1.50 (m, 4H), 1.34-1.27 (m,8H). First eluting diastereomer purified by Prep-TLC (6% MeOH/DCM). Rf =0.45 I-195 ¹H NMR (400 MHz, CD₃OD) δ 9.24-8.88 (m, 1H), 8.57-8.32 m/z =696.4 (m, 2H), 7.97-7.88 (m, 1H), 7.28-6.81 (m, 8H), 4.80-4.15 [M + H]⁺(m, 4H), 3.87-3.33 (m, 7H), 3.06-2.35 (m, 9H), 2.07-1.51 (m, 3H),1.35-1.23 (m, 8H). Second eluting diastereomer purified by Prep-TLC (6%MeOH/DCM). Rf = 0.4 I-196 ¹H NMR (400 MHz, CD₃OD) δ 9.03-8.73 (m, 2H),7.31-6.78 m/z = 691.3 (m, 8H), 4.74-4.10 (m, 3H), 3.91-3.36 (m, 9H),3.27-2.92 [M + H]⁺ (m, 1H), 2.84-2.37 (m, 8H), 1.84-1.56 (m, 3H),1.38-1.23 (m, 9H). I-197 ¹H NMR (400 MHz, CD₃OD) δ 7.30-6.49 (m, 9H),4.66-4.14 m/z = 679.4 (m, 3H), 3.89-3.56 (m, 6H), 3.52-3.33 (m, 2H),2.81-2.54 [M + H]⁺ (m, 7H), 1.84-1.48 (m, 3H), 1.39-1.21 (m, 11H). I-198¹H NMR (400 MHz, CD₃OD) δ 7.75-6.93 (m, 9H), 6.30-6.13 m/z = 659.5 (m,1H), 4.74-4.36 (m, 2H), 4.35-3.97 (m, 2H), 3.93-3.75 [M + H]⁺ (m, 4H),3.72-3.35 (m, 4H), 3.26-2.97 (m, 2H), 2.76-2.49 (m, 7H), 1.80-1.54 (m,4H), 1.41-1.23 (m, 8H) I-199 ¹H NMR (400 MHz, CD₃OD) δ 8.43-6.43 (m,12H), 4.74-3.33 m/z = 694.5 (m, 12H), 3.25-2.34 (m, 8H), 2.04-1.47 (m,3H), 1.45-1.19 [M + H]⁺ (m, 8H). I-200 ¹H NMR (400 MHz, CD₃OD) δ7.37-6.70 (m, 12H), 4.75-4.25 m/z = 738.5 (m, 3H), 4.20-3.76 (m, 9H),3.70-3.35 (m, 3H), 3.24-2.96 [M + H]⁺ (m, 2H), 2.94-2.51 (m, 7H),2.46-2.36 (m, 1H), 1.77-1.55 (m, 3H), 1.40-1.24 (m, 8H). I-201 ¹H NMR(400 MHz, CD₃OD) δ 7.50-6.73 (m, 12H), 4.80-3.90 m/z = 722.4 (m, 4H),3.88-3.47 (m, 4H), 3.69-3.35 (m, 3H), 3.28-2.49 [M + H]⁺ (m, 9H),2.44-2.29 (m, 4H), 1.91-1.45 (m, 4H), 1.42-1.23 (m, 8H). I-202 ¹H NMR(400 MHz, CD₃OD) δ 8.56-8.40 (m, 2H), 7.44-6.87 m/z = 670.4 (m, 10H),4.67-4.13 (m, 3H), 4.07-3.45 (m, 9H), 3.24-2.81 [M + H]⁺ (m, 2H),2.76-2.40 (m, 7H), 1.83-1.42 (m, 4H), 1.37-1.22 (m, 8H). I-203 ¹H NMR(400 MHz, CD₃OD) δ 7.91-6.65 (m, 12H), 4.77-4.06 m/z = 733.5 (m, 3H),4.04-3.34 (m, 9H), 3.29-2.72 (m, 3H), 2.71-2.21 [M + H]⁺ (m, 7H), 1.63(m, 3H), 1.40-1.23 (m, 8H). I-204 ¹H NMR (400 MHz, CD₃OD) δ 7.83-6.80(m, 12H), 4.77-3.79 m/z = 743.4 (m, 9H), 3.76-3.34 (m, 4H), 3.29-2.86(m, 2H), 2.75-2.57 [M + H]⁺ (m, 6H), 2.46-2.30 (m, 1H), 1.78-1.52 (m,3H), 1.40-1.28 (m, 7H), 0.94-0.86 (m, 1H). I-205 ¹H NMR (400 MHz, CD₃OD)δ 7.88-6.35 (m, 11H), 4.75-3.39 m/z = 743.4 (m, 12H), 3.27-2.50 (m 9H),2.44-2.20 (m, 1H), 1.82-1.21 [M + H]⁺ (m, 11H). I-206 ¹H NMR (400 MHz,CD₃OD) δ 9.20-9.05 (m, 1H), 8.25-8.10 m/z = 662.4 (m, 1H), 7.29-6.82 (m,8H), 4.68-3.35 (m, 12H), 2.82-2.36 [M + H]⁺ (m, 8H), 1.77-1.50 (m, 3H),1.38-1.21 (m, 8H). I-207 ¹H NMR (400 MHz, CD₃OD) δ 7.30-6.80 (m, 8H),4.68-3.74 m/z = 663.5 (m, 11H), 3.72-3.36 (m, 5H), 3.23-2.30 (m, 9H),1.88-1.52 [M + H]⁺ (m, 7H), 1.37-1.23 (m, 8H). I-208 ¹H NMR (400 MHz,CD₃OD) δ 9.01-8.74 (m, 1H), 8.36-8.20 m/z = 681.4 (m, 1H), 7.85-7.69 (m,1H), 7.29-6.81 (m, 8H), 4.72-4.12 [M + H]⁺ (m, 3H), 3.94-3.33 (m, 9H),3.28-3.02 (m, 1H), 2.89-2.36 (m, 8H), 1.84-1.53 (m, 3H), 1.40-1.20 (m,8H). I-209 ¹H NMR (400 MHz, CD₃OD) δ 8.04-7.86 (m, 1H), 7.70-7.40 m/z =686.4 (m, 2H), 7.29-6.82 (m, 8H), 4.83-4.10 (m, 5H), 4.04-3.34 (m, [M +H]⁺ 9H), 3.28-2.92 (m, 2H), 2.80-2.36 (m, 7H), 1.83-1.55 (m, 3H),1.42-1.19 (m, 7H). I-210 ¹H NMR (400 MHz, CD₃OD) δ 9.28-8.67 (m, 3H),8.20-7.52 m/z = 732.5 (m, 5H), 7.30-6.82 (m, 8H), 4.70-3.36 (m, 12H),2.85-2.35 (m, [M + H]⁺ 8H), 1.82-1.56 (m, 2H), 1.45-1.22 (m, 8H). I-211¹H NMR (400 MHz, CD₃OD) δ 8.69-8.44 (m, 2H), 7.30-6.82 m/z = 671.4 (m,8H), 4.74-3.34 (m, 12H), 3.27-2.98 (m, 1H), 2.87-2.33 (m, [M + H]⁺ 11H),1.86-1.58 (m, 3H), 1.37-1.23 (m, 7H). I-212 ¹H NMR (400 MHz, CD₃OD) δ8.81-8.64 (m, 1H), 8.12-8.05 m/z = 709.4 (m, 1H), 7.86-7.46 (m, 2H),7.28-6.82 (m, 8H), 4.71-3.78 [M + H]⁺ (m, 9H), 3.68-3.36 (m, 3H),3.26-2.92 (m, 2H), 2.84-2.57 (m, 6H), 2.51-1.98 (m, 2H), 1.75-1.52 (m,3H), 1.39-1.26 (m, 8H). I-213 ¹H NMR (400 MHz, CDCl₃) δ 7.76-7.62 (m,1H), 7.37-6.94 m/z = 694.5 (m, 10H), 6.88-6.74 (m, 1H), 6.61-6.50 (m,1H), 4.63-4.20 [M + H]⁺ (m, 2H), 4.04-3.27 (m, 10H), 3.25-2.45 (m, 8H),2.06-1.50 (m, 5H), 1.45-1.29 (m, 7H). I-214 ¹H NMR (400 MHz, CD₃OD) δ8.59-6.76 (m, 11H), 4.72-3.39 m/z = 684.5 (m, 12H), 3.21-2.33 (m, 11H),1.83-1.52 (m, 3H), 1.42-1.21 [M + H]⁺ (m, 10H). I-215 ¹H NMR (400 MHz,CD₃OD) δ 7.28-6.22 (m, 11H), 4.66-4.18 m/z = 658.4 (m, 4H), 3.87-3.79(m, 3H), 3.79-3.58 (m, 5H), 3.49-3.33 [M + H]⁺ (m, 2H), 2.76-2.36 (m,8H), 1.82-1.54 (m, 3H), 1.35-1.25 (m, 9H). I-216 ¹H NMR (400 MHz, CD₃OD)δ 7.87-7.68 (m, 1H), 7.35-6.82 m/z = 687.4 (m, 9H), 4.73-4.46 (m, 2H),4.43-4.20 (m, 1H), 4.19-3.92 [M + H]⁺ (m, 4H), 3.87-3.34 (m, 8H),3.27-2.38 (m, 9H), 1.77-1.47 (m, 3H), 1.37-1.25 (m, 8H). I-217 ¹H NMR(400 MHz, CD₃OD) δ 7.28-6.67 (m, 12H), 4.70-3.33 m/z = 722.5 (m, 13H),3.27-2.93 (m, 2H), 2.79-2.36 (m, 10H), 1.79-1.52 [M + H]⁺ (m, 3H),1.39-1.23 (m, 8H). I-218 ¹H NMR (400 MHz, CD₃OD) δ 7.96-6.45 (m, 13H),4.72-3.36 m/z = 766.5 (m, 16H), 3.26-2.15 (m, 13H), 1.81-1.17 (m, 11H).[M + H]⁺ I-219 ¹H NMR (400 MHz, CD₃OD) δ 7.47-6.70 (m, 12H), 4.75-3.39m/z = 722.5 (m, 11H), 3.27-2.33 (m, 13H), 1.82-1.52 (m, 3H), 1.45-1.18[M + H]⁺ (m, 9H). I-220 ¹H NMR (400 MHz, CD₃OD) δ 7.74-6.57 (m, 12H),4.65-3.97 m/z = 742.3 (m, 4H), 3.96-3.65 (m, 6H), 3.63-3.36 (m, 2H),3.24-2.77 [M + H]⁺ (m, 2H), 2.76-2.36 (m, 7H), 2.33-1.93 (m, 1H), 1.64(m, 4H), 1.35-1.19 (m, 7H). I-221 ¹H NMR (400 MHz, CD₃OD) δ 7.35-6.85(m, 12H), 4.72-3.35 m/z = 742.3 (m, 12H), 3.27-2.82 (m, 2H), 2.81-2.24(m, 8H), 1.89-1.42 [M + H]⁺ (m, 4H), 1.35-1.22 (m, 7H). I-222 ¹H NMR(400 MHz, CD₃OD) δ 7.63-6.76 (m, 12H), 4.75-3.37 m/z = 742.3 (m, 11H),3.30-3.00 (m, 2H), 2.99-2.24 (m, 8H), 2.01-1.46 [M + H]⁺ (m, 4H),1.43-1.19 (m, 8H). I-223 ¹H NMR (400 MHz, CD₃OD) δ 7.68-6.69 (m, 13H),4.73-3.76 m/z = 708.4 (m, 9H), 3.75-3.32 (m, 3H), 3.26-2.90 (m, 2H),2.77-2.45 [M + H]⁺ (m, 6H), 2.43-2.34 (m, 1H), 2.32-1.85 (m, 1H),1.79-1.38 (m, 4H), 1.38-1.22 (m, 7H). I-224 ¹H NMR (400 MHz, CD₃OD) δ8.53-8.33 (m, 2H), 7.81-7.66 m/z = 670.4 (m, 1H), 7.47-6.83 (m, 9H),4.75-3.80 (m, 9H), 3.79-3.38 [M + H]⁺ (m, 4H), 2.77-2.54 (m, 7H),2.46-2.34 (m, 1H), 1.73-1.44 (m, 4H), 1.39-1.25 (m, 8H). I-225 ¹H NMR(400 MHz, CD₃OD) δ 7.67-6.64 (m, 12H), 4.77-3.79 m/z = 756.5 (m, 9H),3.77-3.63 (m, 3H), 3.62-3.36 (m, 3H), 3.27-3.02 [M + H]⁺ (m, 2H),2.97-2.79 (m, 1H), 2.77-2.55 (m, 6H), 2.44-2.37 (m, 1H), 2.24-2.00 (m,1H), 1.86-1.50 (m, 4H), 1.41-1.26 (m, 8H). I-226 ¹H NMR (400 MHz, CD₃OD)δ 7.74-6.31 (m, 12H), 4.77-4.11 m/z = 756.5 (m, 4H), 4.08-3.38 (m, 6H),3.26-2.81 (m, 2H), 2.81-2.07 [M + H]⁺ (m, 9H), 2.07-1.55 (m, 3H),1.54-1.16 (m, 12H). I-227 ¹H NMR (400 MHz, CD₃OD) δ 7.97-6.38 (m, 11H),4.75-3.90 m/z = 776.4 (m, 4H), 3.87-3.40 (m, 7H), 3.20-2.52 (m, 8H),2.46-1.51 [M + H]⁺ (m, 5H), 1.42-1.17 (m, 10H). I-228 ¹H NMR (400 MHz,CD₃OD) δ 7.64-6.79 (m, 12H), 4.66-4.08 m/z = 708.4 (m, 3H), 3.89-3.34(m, 8H), 3.29-2.34 (m, 12H), 1.85-1.46 [M + H]⁺ (m, 3H), 1.43-1.17 (m,8H). I-229 ¹H NMR (400 MHz, CD₃OD) δ 7.31-6.54 (m, 12H), 4.74-3.97 m/z =738.4 (m, 4H), 3.96-3.69 (m, 8H), 3.67-3.36 (m, 3H), 3.27-2.78 [M + H]⁺(m, 3H), 2.79-1.91 (m, 8H), 1.75-1.43 (m, 3H), 1.39-1.23 (m, 7H). I-230¹H NMR (400 MHz, CD₃OD) δ 8.65-8.31 (m, 3H), 7.28-6.88 m/z = 671.5 (m,8H), 4.73-3.35 (m, 14H), 3.25-2.33 (m, 10H), 1.80-1.54 [M + H]⁺ (m, 3H),1.38-1.26 (m, 8H). I-231 ¹H NMR (400 MHz, CD₃OD) δ 7.59-6.69 (m, 12H),4.83-3.38 m/z = 722.5 (m, 12H), 3.29-2.21 (m, 14H), 2.02-1.58 (m, 3H),1.49-1.21 [M + H]⁺ (m, 8H). I-232 ¹H NMR (400 MHz, CD₃OD) δ 8.41 (m,1H), 7.27-6.84 (m, m/z = 680.4 9H), 4.68-4.19 (m, 4H), 3.87-3.77 (m,4H), 3.70-3.57 (m, [M + H]⁺ 2H), 2.78-2.58 (m, 7H), 2.48-2.36 (m, 2H),1.74-1.57 (m, 2H), 1.36-1.22 (m, 9H). First eluting diastereomerpurified by prep-HPLC on an Agilent 10 Prep-C18 column (21.2 mm I.D. ×25 cm, 10 um), using H₂O/ACN 0.1% TFA at a flow rate of 20 mL/min (wavelength 214 nm). Rt = 10.1 min I-233 ¹H NMR (400 MHz, CD₃OD) δ 8.48-8.33(m, 1H), 7.32-6.93 m/z = 680.4 (m, 9H), 4.79-4.15 (m, 4H), 3.86-3.80 (m,3H), 3.69-3.57 [M + H]⁺ (m, 3H), 3.50-3.42 (m, 1H), 2.81-2.55 (m, 8H),1.78-1.58 (m, 4H), 1.36-1.28 (m, 8H). Second eluting diastereomerpurified by prep-HPLC on an Agilent 10 Prep-C18 column (21.2 mm I.D. ×25 cm, 10 um), using H₂O/ACN 0.1% TFA at a flow rate of 20 mL/min (wavelength 214 nm). Rt = 11.8 min I-234 ¹H NMR (400 MHz, CD₃OD) δ 7.57-6.47(m, 12H), 4.75-3.72 m/z = 778.5 (m, 11H), 3.66-3.33 (m, 3H), 3.23-2.68(m, 5H), 2.66-2.36 [M + H]⁺ (m, 5H), 2.01-1.53 (m, 4H), 1.45-1.20 (m,9H), 0.62-0.55 (m, 2H), 0.37-0.28 (m, 2H). I-235 ¹H NMR (400 MHz, CD₃OD)δ 7.61-6.49 (m, 12H), 4.65-4.23 m/z = 738.4 (m, 2H), 4.20-3.74 (m, 9H),3.73-3.34 (m, 3H), 3.21-2.85 [M + H]⁺ (m, 2H), 2.82-2.15 (m, 8H),2.07-1.44 (m, 4H), 1.40-1.23 (m, 8H). I-236 ¹H NMR (400 MHz, CD₃OD) δ7.83-6.37 (m, 13H), 4.72-4.14 m/z = 734.5 (m, 3H), 3.92-3.74 (m, 3H),3.67-3.42 (m, 1H), 3.27-2.22 [M + H]⁺ (m, 11H), 1.85-1.27 (m, 11H),1.27-0.72 (m, 6H). I-237 ¹H NMR (400 MHz, CD₃OD) δ 7.99-6.52 (m, 12H),4.79-3.78 m/z = 786.3 (m, 9H), 3.74-3.35 (m, 4H), 3.26-2.14 (m, 11H),1.77-1.53 [M + H]⁺ (m, 3H), 1.33 (m, 6H).

Synthesis ofN-(5-benzylpyridin-3-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-238

Step 1: To a solution of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid (100 mg, 0.18 mmol; see synthesis of 1-88) in DCM (3 mL) was addedDCC (31.0 mg, 0.27 mmol) and HOSu (42 mg, 0.36 mmol). The mixture wasstirred for 8 h. The resulting mixture was filtered and concentrated toafford the active ester as a white solid. LCMS m/z=651.2 [M+H]⁺.

Step 2: To a solution of 5-benzylpyridin-3-amine (50 mg, 0.077 mmol) inTHF (5 mL) was added LiHMDS (2M in THF, 0.153 mmol) dropwise at 0° C.After stirring for 30 min, the active ester was added to the mixture andstirred 1-238 (5 mg, 10%) as a white solid. LCMS m/z=720.3 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ 9.20-8.89 (m, 1H), 8.46-8.30 (m, 1H), 8.20-7.80(m, 1H), 7.63-6.72 (m, 12H), 4.77-4.42 (m, 1H), 4.38-4.05 (m, 3H),4.02-3.88 (m, 2H), 3.87-3.55 (m, 6H), 3.55-3.33 (m, 2H), 3.25-3.09 (m,1H), 2.96-1.99 (m, 4H), 1.46-1.20 (m, 8H).

The compounds listed in Table 5 were synthesized using analogous methodsto those shown for 1-238, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers.

TABLE 5 Compounds made by a method analogous to I-229 # ¹H NMR LCMSI-239 ¹H NMR (400 MHz, CD₃OD) δ 9.07-6.28 (m, 15H), 4.79-4.19 m/z =720.3 (m, 3H), 4.19-3.35 (m, 11H), 3.27-3.00 (m, 1H), 2.96-1.99 [M + H]⁺(m, 4H), 1.45-1.18 (m, 7H). I-240 ¹H NMR (400 MHz, CD₃OD) δ 8.51-8.29(m, 1H), 8.08-7.68 m/z = 722.3 (m, 2H), 7.57-7.26 (m, 4H), 7.24-6.69 (m,8H), 4.81-4.29 (m, [M + H]⁺ 2H), 4.27-3.70 (m, 7H), 3.60-3.47 (m, 2H),3.27-2.24 (m, 5H), 1.42-1.25 (m, 7H). I-241 ¹H NMR (400 MHz, CD₃OD) δ9.25-8.90 (m, 1H), 8.32-8.06 m/z = 720.4 (m, 1H), 7.72-6.75 (m, 13H),4.80-4.23 (m, 4H), 4.06-3.35 [M + H]⁺ (m, 10H), 3.23-3.03 (m, 1H),2.90-2.61 (m, 2H), 2.57-2.34 (m, 1H), 1.68-0.98 (m, 8H).

Synthesis of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-N-((2S,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)-2-(4-cyclopropoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-242

Step 1: ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate

To a solution of 2-(tert-butyl) 7-ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate(500 mg, 1.02 mmol; see synthesis of I-1) in DCM (10 mL) was added HCl(4M in dioxane, 10 mL). The resulting mixture was stirred for 2 h. Thesolvent was removed to afford the product (500 mg, quant.). LCMSm/z=390.2 [M+H]⁺.

Step 2: ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-cyclopropoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate

In a similar manner to the procedure reported in Step 1 of thepreparation of I-1, the coupling of ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylateand 4-cyclopropoxybenzoic acid gave the product (413 mg, 76%) aftercolumn chromatography (2.5% MeOH/DCM) as a white solid.

Step 3:5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-cyclopropoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid

To a solution of ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-cyclopropoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate(413 mg, 0.753 mmol) in MeOH (5 mL) was added aqueous NaOH (1M, 3 mL).The resulting mixture was stirred for 3 h. The solvent was removed undervacuum, the residue diluted with water and the pH adjusted to 1 byaddition of 1M HCl. The aqueous layer was extracted with EtOAc threetimes. The combined organic layers were washed with water, brine anddried over Na₂SO₄. Removal of the solvent afforded the product (381.0mg, 97%) as a white solid. LCMS m/z=522.3 [M+H]⁺.

Step 4:5-(2-(6-chloro-1H-indol-3-yl)acetyl)-N-((2S,3R)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)-2-(4-cyclopropoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

In a similar manner to the procedure in Step 1 of the preparation ofI-1, the coupling of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-cyclopropoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid and (2S,3R)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamide gave1-242 (40 mg, 51%) after column chromatography (2.8% MeOH/DCM) as awhite solid. LCMS m/z=732.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.06-6.94(m, 8H), 4.68-3.35 (m, 10H), 3.27-2.07 (m, 9H), 1.80-1.58 (m, 5H),1.57-1.39 (m, 1H), 1.38-1.06 (m, 7H), 1.04-0.72 (m, 7H).

The compounds listed in Table 6 were synthesized using analogous methodsto those shown for 1-242, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers.

TABLE 6 Compounds made by a method analogous to I-242 # ¹H NMR LCMSI-243 ¹H NMR (400 MHz, CD₃OD) δ 7.65-6.93 (m, 12H), 4.82-4.26 m/z =730.4 (m, 5H), 4.25-3.33 (m, 8H), 3.27-2.73 (m, 2H), 2.71-2.37 (m, [M +H]⁺ 2H), 1.37-1.28 (m, 2H), 1.20-1.15 (m, 4H), 1.06-0.83 (m, 2H),0.83-0.64 (m, 3H). I-244 ¹H NMR (400 MHz, CD₃OD) δ 7.74-6.87 (m, 12H),4.73-3.34 m/z = 730.4 (m, 13H), 3.28-1.98 (m, 6H), 1.27-1.14 (m, 2H),0.92-0.63 [M + H]⁺ (m, 5H). I-245 ¹H NMR (400 MHz, CD₃OD) δ 7.68-6.89(m, 12H), 4.69-4.27 m/z = 730.4 (m, 4H), 4.21-3.35 (m, 8H), 3.26-1.97(m, 6H), 1.37-0.61 (m, [M + H]⁺ 7H). I-246 ¹H NMR (400 MHz, CD₃OD) δ7.67-6.88 (m, 12H), 4.79-3.35 m/z = 730.4 (m, 12H), 3.26-1.88 (m, 6H),1.28-0.61 (m, 7H) [M + H]⁺

Synthesis of2-(3,4-dichlorobenzoyl)-5-(2-(6-methoxy-1H-indol-3-yl)acetyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-247

Step 1: 2-(tert-butyl) 7-ethyl5-(2-(6-methoxy-1H-indol-3-yl)acetyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate

To a solution of Int-1 (400 mg, 1.34 mmol) in DMA (10 mL) was added2-(6-methoxy-1H-indol-3-yl)acetic acid (330 mg, 1.61 mmol), EDCI (385mg, 2.01 mmol), HOBt (217 mg, 1.61 mmol) and DIPEA (520 mg, 4.02 mmol).The resulting mixture was stirred overnight. Water was added and themixture was extracted with EtOAc three times. The combined organiclayers were washed with water, brine and dried over Na₂SO₄. The solventwas then removed and the crude purified by column chromatography (2%MeOH/DCM) to afford the product (410 mg, 63%) as a white solid. LCMSm/z=486 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.46 (dd, J=21.3, 8.6 Hz, 1H),7.07-6.99 (m, 1H), 6.92-6.85 (m, 1H), 6.69 (td, J=8.5, 3.9 Hz, 1H), 4.60(s, 1H), 4.31 (dt, J=16.2, 12.8 Hz, 1H), 4.20-3.94 (m, 3H), 3.80 (d,J=4.9 Hz, 3H), 3.73 (t, J=13.9 Hz, 1H), 3.31 (dq, J=4.2, 2.9, 2.2 Hz,3H), 3.05 (s, 3H), 2.92 (s, 3H), 1.45-1.36 (m, 9H), 1.28-1.17 (m, 3H).

Step 2: ethyl5-(2-(6-methoxy-M-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylatehydrochloride

To a solution of 2-(tert-butyl) 7-ethyl5-(2-(6-methoxy-1H-indol-3-yl)acetyl)octahydro-2H-pyrrolo[3,4-c]pyridine-2,7-dicarboxylate(410 mg, 0.84 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 3 mL).The resulting mixture was stirred for 3 h. The solvent was removed toafford the target compound (443 mg, quant.). LCMS m/z=386 [M+H]⁺.

Step 3: ethyl2-(3,4-dichlorobenzoyl)-5-(2-(6-methoxy-M-indol-3-yl)acetyl)octahydro-M-pyrrolo[3,4-c]pyridine-7-carboxylate

In a similar manner to the procedure in Step 1, the coupling of ethyl5-(2-(6-methoxy-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylatehydrochloride and 3,4-dichlorobenzoic acid gave the desired product (86mg, 26%) after column chromatography (2% MeOH/DCM) as a white solid.LCMS m/z=558 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.30-6.46 (m, 7H),4.54-4.08 (m, 1H), 4.08-3.83 (m, 1H), 3.82-3.61 (m, 4H), 3.61-3.34 (m,2H), 3.28-3.12 (m, 1H), 3.12-2.88 (m, 1H), 2.81-2.32 (m, 2H), 2.30-1.19(m, 6H), 1.18-0.61 (m, 3H).

Step 4:2-(3,4-dichlorobenzoyl)-5-(2-(6-methoxy-M-indol-3-yl)acetyl)octahydro-M-pyrrolo[3,4-c]pyridine-7-carboxylicacid

To a solution of ethyl2-(3,4-dichlorobenzoyl)-5-(2-(6-methoxy-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate(86 mg, 0.15 mmol) in MeOH (3 mL) was added aqueous NaOH (1M, 3 mL). Themixture was stirred at room temperature for 5 h then the solvent wasremoved under vacuum. The residue obtained was diluted with water andthe pH adjusted to ˜1 by addition of 1M HCl. The aqueous layer wasextracted with EtOAc three times and the combined organic layers werewashed with water, brine and dried over Na₂SO₄. Removal of the solventafforded the product (48 mg, 59%) as a white solid. LCMS m/z=530 [M+H]⁺.

Step 5:2-(3,4-dichlorobenzoyl)-5-(2-(6-methoxy-1H-indol-3-yl)acetyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

In a similar manner to the procedure in Step 1, the coupling of2-(3,4-dichlorobenzoyl)-5-(2-(6-methoxy-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid and (S)-2-amino-N-methyl-5-phenylpentanamide gave 1-247 (10 mg,15%) after column chromatography (2% MeOH/DCM) as a white solid. LC-MSm/z=718.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.77-6.60 (m, 12H),4.66-4.01 (m, 3H), 4.01-3.70 (m, 5H), 3.69-3.44 (m, 2H), 3.43-3.33 (m,1H), 3.29-2.14 (m, 11H), 2.06-1.31 (m, 5H).

The compounds listed in Table 7 were synthesized using analogous methodsto those shown for 1-247, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers.

TABLE 7 Compounds made by a method analogous to I-247 Example ¹H NMRLCMS I-248 ¹H NMR (400 MHz, CD₃OD) δ 8.56-6.39 (m, 12H), 4.60-4.20 m/z =751.2 (m, 2H), 4.19-3.98 (m, 1H), 3.98-3.64 (m, 5H), 3.62-3.36 (m, [M +H]⁺ 2H), 3.31-2.78 (m, 4H), 2.76-2.60 (m, 5H), 2.57-2.36 (m, 2H),2.03-1.33 (m, 5H), 1.25-0.74 (m, 1H).

Synthesis of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-N-((2S,3S)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-249

Step 1: ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate

To a solution of ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate(358 mg, 0.92 mmol; see synthesis of 1-242) in DMF (5.0 mL) was added3-phenyl-1H-pyrazole-5-carboxylic acid (207 mg, 1.1 mmol), EDCI (264 mg,1.38 mmol), HOBt (186 mg, 1.38 mmol) and DIPEA (593 mg, 4.59 mmol). Theresulting mixture was stirred for 14 h. Water was then added and theaqueous extracted with EtOAc three times. The combined organic layerswere washed with water and brine and dried over Na₂SO₄. The solvent wasremoved and the crude purified by column chromatography (2% MeOH/DCM) togive ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate(350 mg, 68%) as a yellow solid.

Step 2:5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid

To the solution of ethyl5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylate(350 mg, 0.62 mmol) in a mixture of THF and H₂O (5.0 mL/1.0 mL) wasadded NaOH (75 mg, 1.87 mmol) and the solution was stirred for 4 h. ThepH was adjusted to 2 by addition of 1N HCl then concentrated to give theproduct (450 mg, quant.) as a white solid. LCMS m/z=532.1 [M+H]⁺.

Step 3:5-(2-(6-chloro-1H-indol-3-yl)acetyl)-N-((2S,3S)-3-(cyclohexylmethoxy)-1-(methylamino)-1-oxobutan-2-yl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

In a similar manner reported for synthesis of the product of Step 1, thecoupling of5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(3-phenyl-1H-pyrazole-5-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid and (2S,3S)-2-amino-3-(cyclohexylmethoxy)-N-methylbutanamideafforded 1-249 (20 mg, 28%) as a white solid after prep-TLC (6%MeOH/DCM). LCMS m/z=742.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.00-6.80(m, 10H), 4.65-3.40 (m, 11H), 3.25-2.46 (m, 9H), 1.79-1.54 (m, 5H),1.26-0.73 (m, 10H).

The compounds listed in Table 8 were synthesized using analogous methodsto those shown for I-249, using the appropriate commercially availablereagents and/or intermediates. Final examples were obtained as a mixtureof diastereomers.

TABLE 8 Compounds made by a method analogous to I-249 Example ¹H NMRChromatography conditions, if applicable LCMS I-250 ¹H NMR (400 MHz,CD₃OD) δ 8.07-6.74 (m, 15H), 4.71-3.45 m/z = 736.5 (m, 13H), 3.29-2.03(m, 9H), 1.48-1.37 (m, 1H), 1.29-1.03 (m, [M + H]⁺ 3H) I-251 ¹H NMR (400MHz, CD₃OD) δ 8.00-6.73 (m, 10H), 4.67-3.42 m/z = 742.4 (m, 11H),3.24-2.21 (m, 10H), 1.82-1.39 (m, 6H), 1.22-0.83 (m, [M + H]⁺ 7H). I-252¹H NMR (400 MHz, CD₃OD) δ 7.91-6.73 (m, 15H), 4.69-4.33 m/z = 736.5 (m,4H), 4.28-3.72 (m, 6H), 3.70-3.47 (m, 2H), 3.23-2.74 (m, [M + H]⁺ 3H),2.71-2.44 (m, 4H), 2.44-1.85 (m, 1H), 1.25-0.83 (m, 4H).

Synthesis of2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)-5-(2-(quinolin-4-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-253

Step 1: 4-(2,2-dibromovinyl)quinoline

A mixture of quinoline-4-carbaldehyde (500 mg, 3.18 mmol), carbontetrabromide (3.16 g, 9.54 mmol) and triphenylphosphine (5.19 g, 19.08mmol) in DCM (10 mL) wad stirred at room temperature for 1.5 h under anatmosphere of N2. Water was added and the aqueous extracted with EtOAc.The combined organic layers were washed with water, brine and dried overNa₂SO₄. The solvent was removed and the residue purified by columnchromatography (6% MeOH/DCM) to afford 4-(2,2-dibromovinyl)quinoline(45.5 mg, 4.6%) as a brown solid.

Step 2:2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)-5-(2-(quinolin-4-yl)acetyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

To a solution of 4-(2,2-dibromovinyl)quinoline (25 mg, 0.08 mmol) in DMF(1.5 ml) and H₂O (0.5 mL) was added2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(45 mg, 0.08 mmol; see synthesis of 1-154) and DIEA (31 mg, 0.24 mmol).The resulting mixture was stirred at room temperature for 4 h. Water wasadded and the aqueous extracted with EtOAc three times. The combinedorganic layers were washed with water, brine and dried over Na₂SO₄. Thesolvent was removed and the residue purified by prep-HPLC to afford theproduct (31 mg, 48%) as a yellow solid. LCMS m/z=720.4 [M+H]⁺ ¹H NMR(400 MHz, CD₃OD) δ 9.22-9.00 (m, 1H), 8.45-7.83 (m, 5H), 7.29-6.83 (m,8H), 4.72-3.37 (m, 13H), 3.22-2.00 (m, 9H), 1.92-1.18 (m, 11H).

Synthesis of5-(2-(6-chloro-1H-indol-3-yl)ethyl)-2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-254

Step 1: methyl 2-(6-chloro-1H-indol-3-yl)acetate

To a solution of 2-(6-chloro-1H-indol-3-yl)acetic acid (210 mg, 1.0mmol) in MeOH (5.0 mL) was added con. H₂SO₄ (3 mL). The mixture washeated at 65° C. for 1 h. The mixture was poured into ice-water and theaqueous extracted with EtOAc three times. The combined organic layerswere washed with water, brine and dried over Na₂SO₄. The solvent wasremove and the residue purified by column chromatography (20% EtOAc/PE)to afford methyl 2-(6-chloro-1H-indol-3-yl)acetate (121 mg, 54%) as awhite solid.

Step 2: 2-(6-chloro-1H-indol-3-yl)acetaldehyde

To a solution of methyl 2-(6-chloro-1H-indol-3-yl)acetate (121 mg, 0.54mmol) in DCM (1.0 mL) at −78° C. was added DIBAL-H (4M in Toluene, 0.2mL). The resulting mixture was stirred at −78° C. under N₂ for 3 h. Thereaction mixture was quenched with saturated aq. NH₄Cl and the aqueousextracted with EtOAc three times. The combined organic layers werewashed with water, brine and dried over Na₂SO₄. The solvent was removedand the residue purified by column chromatography (33% EtOAc/PE) toafford 2-(6-chloro-1H-indol-3-yl)acetaldehyde (26 mg, 25% yield) as awhite solid.

Step 3:5-(2-(6-chloro-1H-indol-3-yl)ethyl)-2-(4-isopropoxy-3-methoxybenzoyl)-N4S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

To2-(4-isopropoxy-3-methoxybenzoyl)-N—((S)-1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(50 mg, 0.09 mmol; see synthesis of I-154) and2-(6-chloro-1H-indol-3-yl)acetaldehyde (12.0 mg, 0.06 mmol) in DCE (2.0mL) was added NaBH(OAc)₃ (38.5 mg, 0.18 mmol) and the mixture stirred atroom temperature overnight. The reaction mixture was concentrated invacuo and the residue purified by prep-HPLC to afford the product (11.2mg, 25.4%) as a white solid. LCMS m/z=728.5 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ 7.59-6.74 (m, 12H), 4.68-3.91 (m, 3H), 3.87-3.79 (m, 3H),3.72-3.34 (m, 4H), 2.96-2.89 (m, 2H), 2.82-2.76 (m, 1H), 2.75-2.51 (m,8H), 2.49-2.39 (m, 2H), 1.79-1.50 (m, 4H), 1.36-1.28 (m, 8H).

Synthesis of methyl(2S,3S)-3-(benzyloxy)-2-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamido)butanoateI-255

A mixture of methyl O-benzyl-L-allothreoninate (60.45 mg, 0.271 mmol),5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxylicacid (100 mg, 0.181 mmol) (1-88, Step 3), EDCI (52.0 mg, 0.271 mmol),HOBt (36.6 mg, 0.271 mmol) and DIEA (70.0 mg, 0.542 mmol) in DMF (5 mL)was stirred at room temperature overnight. Water was added and theaqueous extracted with EtOAc three times. The combined organic layerswere washed with water and brine and dried over Na₂SO₄. The residueobtained after concentration was purified by prep-HPLC to afford methyl(2S,3S)-3-(benzyloxy)-2-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamido)butanoate(80 mg, 58%) as a white solid. LCMS m/z=759.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ 8.75-6.58 (m, 12H), 4.79-4.47 (m, 3H), 4.40-3.98 (m, 2H),3.98-3.60 (m, 8H), 3.59-3.35 (m, 3H), 3.17-2.97 (m, 2H), 2.83-1.98 (m,4H), 1.62-1.19 (m, 8H), 1.15-1.05 (m, 1H), 0.94-0.67 (m, 2H).

Synthesis ofO-benzyl-N-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonyl)-L-allothreonineI-256

To a solution of I-255 in MeOH (5 mL) was added aqueous NaOH (1 M, 2mL). The resulting mixture was stirred for 3 h then solvent was removedunder vacuum. The residue obtained was diluted with water and the pHadjusted to ˜1 by addition of 1 M HCl. The aqueous layer was extractedwith EtOAc three times and the combined organic layers were washed withwater, brine, dried over Na₂SO₄ and concentrated to affordO-benzyl-N-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carbonyl)-L-allothreonine(500 mg, 90%) as a white solid. LCMS m/z=745.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ 7.78-6.64 (m, 12H), 4.80-4.39 (m, 3H), 4.38-3.95 (m, 2H),3.94-3.68 (m, 5H), 3.67-3.37 (m, 3H), 3.24-2.96 (m, 1H), 2.92-2.16 (m,3H), 1.45-1.37 (m, 3H), 1.36-1.10 (m, 8H), 0.97-0.67 (m, 2H). LCMSm/z=745.4 [M+H]⁺.

Synthesis ofN—((S)-1-((5-aminopentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamideI-257 and 1-258

Step 1: (9H-fluoren-9-yl)methyl(5-((2S)-2-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamido)-5-(3-hydroxyphenyl)pentanamido)pentyl)carbamate

Made using the same procedure reported for preparation of 1-255 using(9H-fluoren-9-yl)methyl(S)-(5-(2-amino-5-(3-hydroxyphenyl)pentanamido)pentyl)carbamate. Twodiastereomers (30 mg each) were obtained after silica gel column (50%EtOAc/PE). LCMS m/z=1051.3 [M+H]⁺.

Step 2:N—((S)-1-((5-aminopentyl)amino)-5-(3-hydroxyphenyl)-1-oxopentan-2-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

To a solution of the first eluting diastereomer from Step 1 (40 mg,0.038 mmol) in dioxane (1 mL) was added aq. NH₄OH (1 mL) and the mixturewas heated at 65° C. in a sealed tube overnight. The solvent was removedunder reduced pressure and the residue was purified by prep-HPLC toafford 1-257 (5.4 mg, 19%) as colorless solid. LCMS m/z=829.5 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ 7.62-6.48 (m, 11H), 4.70-3.75 (m, 9H), 3.69-3.35(m, 3H), 3.22-2.74 (m, 6H), 2.69-2.04 (m, 5H), 1.79-1.49 (m, 7H),1.43-1.25 (m, 10H). The second eluting diastermomer of from Step 1 wastreated in the same fashion to afford I-258 (10.8 mg, 38%) as acolorless solid. LCMS m/z=829.5 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ7.72-6.46 (m, 11H), 4.78-4.42 (m, 2H), 4.36-4.01 (m, 2H), 3.97-3.42 (m,8H), 3.26-2.78 (m, 7H), 2.66-2.10 (m, 5H), 1.74-1.22 (m, 16H).

Synthesis of tert-butyl(5-((2S,3S)-3-(benzyloxy)-2-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamido)butanamido)pentyl)carbamateI-259 and I-260

Step 1:N-((2S,3S)-1-((5-azidopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

Made using the procedure reported for I-257/I-258, Step 1, using(2S,3S)-2-amino-N-(5-azidopentyl)-3-(benzyloxy)butanamide to give thetitled product (100 mg, 20%) as a yellow solid. LCMS m/z=855.3 [M+H]⁺.

Step 2:N-((2S,3S)-1-((5-aminopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide

To a solution of N-((2S,3S)-1-((5-azidopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(270 mg, 0.31 mmol) in a mixture of THF (2 mL) and H₂O (1 mL) was addedPPh₃ (162 mg, 0.62 mmol). The resulting mixture was stirred at roomtemperature for 14 hours. The solvent was removed and the residuepurified by prep-HPLC to afford the titled product (174 mg, 68%) as awhite solid. LCMS m/z=829.5 [M+H]⁺.

Step 3: tert-butyl(5-((2S,3S)-3-(benzyloxy)-2-(5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamido)butanamido)pentyl)carbamate

To a solution ofN-((2S,3S)-1-((5-aminopentyl)amino)-3-(benzyloxy)-1-oxobutan-2-yl)-5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide(25 mg, 0.03 mmol) in DCM (1 mL) was added Boc₂O (6.5 mg, 0.03 mmol) andEt₃N (9 mg, 0.06 mmol). The resulting mixture was stirred at roomtemperature overnight. The solvent was removed in vacuo and the residuepurified by prep-HPLC on an Agilent 10 Prep-C18 column (21.2 mm I.D.×25cm, 10 um), using H₂O/ACN 0.1% TFA, at a flow rate of 20 mL/min (wavelength 214 nm) to afford the first eluting (Rt=9.3 min) diasteromer (16mg, 57%) 1-259 as a white solid; ¹H NMR (400 MHz, CD₃OD) δ 7.63-6.66 (m,12H), 4.73-4.31 (m, 5H), 4.15-3.36 (m, 9H), 3.26-2.90 (m, 6H), 2.87-1.99(m, 5H), 1.43 (s, 9H), 1.39-1.13 (m, 15H). LCMS m/z=929.6 [M+H]⁺, andthe second eluting (Rt=10.5 min) diasteromer (10 mg, 35%) 1-260 also asa white solid; ¹H NMR (400 MHz, CD₃OD) δ 7.67-6.63 (m, 12H), 4.75-3.35(m, 16H), 3.28-2.93 (m, 7H), 2.85-2.44 (m, 3H), 2.29-1.97 (m, 1H), 1.42(s, 9H), 1.38-1.18 (m, 11H), 0.93-0.67 (m, 2H). LCMS m/z=929.6 [M+H]⁺.

Example A1: Caliper Assay

Inhibition of CDK2/Cyclin E1 activity in the presence of compounds ofthe present disclosure was evaluated using a Caliper LabChip® EZ Readermobility shift assay. In the assay, activated CDK2/Cyclin E1 catalyzesthe phosphorylation of a fluorescently tagged peptide 5-FAM-QSPKKG-CONH2(PerkinElmer, FL Peptide 18) which induces a difference in capillaryelectrophoresis mobility. The peptide substrate and product weremeasured, and the conversion ratio was used to determine the inhibition(as % activity and IC₅₀ values) of CDK2/Cyclin E1. Reactions contained50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM EDTA, 2 mM DTT, 0.01% Brij35, 0.5mg/mL BSA, 0.1% DMSO, 2.5 nM CDK2/Cyclin E1(14-475), 100 μM ATP, and 1.5μM fluorescent peptide substrate.

Dose titrations of inhibitors in 100% DMSO were combined with 3.25 nMCDK2/Cyclin E1(14-475) and 130 μM of ATP in reaction buffer. Themixtures were incubated for 30 minutes before the addition offluorescent peptide substrate to initiate the kinase reaction. The finalconditions were 2.5 nM CDK2/Cyclin E1(14-475), 100 μM ATP, and 1.5 μMfluorescent peptide. The reactions were stopped after 100 minutes withthe addition of EDTA (6 mM final EDTA concentration). The stoppedreactions were analyzed on a Caliper LabChip® EZ Reader II. Theconversion ratios were normalized to yield % activity, plotted againstcompound concentration, and fit to a four-parameter equation todetermine the IC₅₀ for each compound.

The results of the Caliper Assay are reported in Table X, below.Compounds with an IC₅₀ less than or equal to 0.5 μM are designated as“A”. Compounds with an IC₅₀ greater than 0.5 μM and less than or equalto 5.0 μM are designated as “B”. Compounds with an IC₅₀ greater than 5.0μM and less than or equal to 10.0 μM are designated as “C”. Compoundswith an IC₅₀ greater than 10.0 μM are designated as “D”.

Example A2: BrdU Cell Proliferation Assay

A BrdU assay was used as a measure of proliferation based on the DNAreplication process of proliferating cells. BrdU, a pyrimidine analog,is added to the cell culture and incorporated into the DNA ofproliferating cells. The presence of the BrdU analog was then measuredthrough a colorimetric ELISA. After fixation and permeabilization ofcells, peroxidase-conjugated antibody recognizing BrdU is added andallowed to incubate, followed by thorough washing to remove unboundantibody. In order to quantify the amount of bound antibody, peroxidasesubstrate is added and produces a color that can be measured at 450 nm.

On day −1, Kuramochi cells (Sekisui XenoTech JCRB0098) were seeded at2,000 cells/well in columns 2-12 of a 96 well plate (Corning, CLS3596)in 150 uL media and allowed to adhere overnight at 37 degree with 5%CO₂. In order to assess specificity of the compounds, Kuramochi RB^(KO)cells were also plated and treated, as RB^(KO) cells were not expectedto show a proliferative response to CCNE/CDK specific inhibitors.

On day 0, the source plate was prepared by adding 10 mM compounds andperforming 3-fold serial dilutions for a 4-point dose response of eachcompound. Using a multichannel pipette, 2 uL of the contents of thesource plate were stamped into an intermediate plate with 500 uL of RPMI1640 Media, GlutaMAX Supplement (Life Technologies, 61870127) in eachwell of a Nunc 96 DeepWell™ plate, non-treated 96 DeepWell plate, 2mL/well, sterile, natural, 60/cs (Sigma Z717274) and mixed thoroughly.50 uL from row A of this intermediate plate were added to rows A-H ofone plate of previously seeded Kuramochi cells, and each subsequent rowof the intermediate plate was added to a full plate of cells.

On day 4, the plates were developed using the BrdU ELISA CellProliferation Assay according to manufacturer's instructions (Roche,11647229001). Briefly, BrdU was diluted 1:100 in Gibco®, Opti-MEM® and20 μL/well was added, shaken for 10 minutes at 350 rpm, and thenreturned to the incubator for 1 hour. Following incubation, the mediumwas discarded, and the cells were fixed by adding 200 μL of Fix/Denaturesolution. The anti-BrdU peroxidase antibody was diluted 1:1000 inOptiMEM, added at 100 μL/well, and incubated while shaking (350 rpm) forone hour. Three washes with PBS were performed to remove any unboundantibody, followed by the addition of 100 μL of substrate solution toeach well. μL/well of 1M sulfuric acid solution was then added to haltthe reaction, and plates were read out using an Envisionspectrophotometer (Perkin Elmer) set to read 450 nm absorbance.Background absorbance values from empty wells were subtracted from allsamples and then normalized to DMSO treated wells.

The results of the BrdU cell proliferation assay are reported in TableX, below. Compounds with an IC₅₀ less than or equal to 0.5 μM aredesignated as “A”. Compounds with an IC₅₀ greater than 0.5 μM and lessthan or equal to 5.0 μM are designated as “B”. Compounds with an IC₅₀greater than 5.0 μM and less than or equal to 10.0 μM are designated as“C”. Compounds with an IC₅₀ greater than 10.0 μM are designated as “D”.

Example A3: HotSpot™ Kinase Inhibition Assay

Inhibition of a select panel of CDK2/CCNE1 activities in the presence ofcompounds of the present disclosure was evaluated using the HotSpot™assay (proprietary to Reaction Biology Corporation). In the assay,activated CDK2/Cyclin E1 catalyzes the transfer of radioactive phosphateto amino acid residues of peptide or protein substrates, which aredetected radiometrically. After subtraction of background derived fromcontrol reactions containing inactive enzyme, kinase activity data isexpressed as the percent remaining kinase activity in test samplescompared to reactions without inhibitor present. Reactions contained 20mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 2 mM DTT, 0.02% Brij35, 0.02mg/mL BSA, 0.1 mM Na₃VO₄, 1% DMSO, 1.5 nM CDK2/Cyclin E1(14-475), 10 μMATP, and 20 μM Histone H1 protein isolated from calf thymus (Sigma).

CDK2/Cyclin E1 (14-75) and Histone H1 were mixed in reaction buffer. Tothis mixture, was added dose titrations of inhibitor compounds in 100%DMSO by acoustic transfer. The compound mixtures were incubated for 20minutes, then the kinase reactions were initiated by the addition of amixture of ATP and ³³P ATP for final concentrations of 10 μM total ATP,20 μM Histone H1, and 1.5 nM CDK2/Cyclin E1 (14-475). The reactions werecarried out for 120 minutes, then spotted on a P81 ion exchange filterpaper, and extensively washed with 0.75% phosphoric acid. The resultingradioactive counts were normalized to yield % activity, plotted againstcompound concentration, and fit to a four-parameter equation todetermine the IC₅₀ for each compound.

The results of the HotSpot™ assay are reported in Table X, below.Compounds with an IC₅₀ less than or equal to 1.0 μM are designated as“A”. Compounds with an IC₅₀ greater than 1.0 μM and less than or equalto 10 μM are designated as “B”. Compounds with an IC₅₀ greater than 10μM and less than or equal to 100 μM are designated as “C”. Compoundswith an IC₅₀ greater than 100 μM are designated as “D”.

Example A4: Incucyte® Cell Proliferation Assay

Kuramochi cells labeled with mApple-H2B and Kuramochi RB1−/− cellslabeled with NucLight green (Sartorius, 4475) were co-plated on 384-wellassay-ready plates along with test compounds at varying concentrations.Plates were placed in the IncuCyte® Sartorius and scanned at 0 and 72hours. IncuCyte® software was used to count the number of fluorescentnuclei in each well. The fold change in cell count from 0 to 72 hours inwells treated with increasing compounds concentrations (10 pts, ½ logdilution, 20 uM top concentration) was normalized to DMSO control wells.The normalized cell counts were fit with dose response curves and a GI₅₀was calculated.

The results of the Incucyte Kuramochi cell viability assay are reportedin Table X, below. Compounds with a GI₅₀ less than or equal to 1.0 μMare designated as “A”. Compounds with a GI₅₀ greater than 1.0 μM andless than or equal to 10.0 μM are designated as “B”. Compounds with aGI₅₀ greater than 10.0 μM and less than or equal to 20.0 μM aredesignated as “C”. Compounds with a GI₅₀ greater than 20.0 μM aredesignated as “D”.

TABLE X Assay Results BrdU Cell Kinase Incucyte ® Cell CaliperProliferation Inhibition Proliferation # Assay Assay Assay Assay I-1 A DI-2 D C I-3 D D I-4 D I-5 D D I-6 B D I-7 B C I-8 D D I-9 C D I-10 D DI-11 D D I-12 D D I-13 D C D I-14 D D I-15 D D I-16 D D I-17 D D I-18 DD I-19 D B A I-20 D D I-21 D D I-22 D D I-23 D D I-24 D D I-25 B D I-26C D I-27 D D I-28 D D I-29 D D I-30 D D I-31 D D I-32 D D I-33 C I-34 CD I-35 D D I-36 D I-37 D D I-38 D D I-39 D D I-40 D D I-41 D D I-42 D DI-43 D D I-44 D D I-45 D D I-46 B D I-47 D D I-48 D D I-49 D I-50 D BI-51 D I-52 C D I-53 D I-54 D D I-55 D D I-56 B D I-57 D D I-58 D D I-59D D I-60 D D I-61 D D I-62 D D I-63 D I-64 D C I-65 D D I-66 D D I-67 CI-68 D I-69 D D I-70 D D I-71 D D I-72 D D I-73 D D I-74 D D I-75 D DI-76 D I-77 D D I-78 D D I-79 C D I-80 D D I-81 D C I-82 B C I-83 A DI-84 B D I-85 A D I-86 D D I-87 A D I-88 D D I-89 D D I-90 D D I-91 B DI-92 D D I-93 B D I-94 D D I-95 B D I-96 D I-97 B D I-98 B D I-99 B DI-100 A B I-101 D D I-102 B D I-103 B D I-104 D D I-105 D D I-106 A B BI-107 A B I-108 D D I-109 B D I-110 D D I-111 A D I-112 C D I-113 B DI-114 D D I-115 C D I-116 D D I-117 B D I-118 D D I-119 D I-120 D I-121D I-122 C I-123 C I-124 D D I-125 C I-126 B D I-127 B D I-128 C B I-129D D I-130 B D I-131 C B I-132 B D I-133 B D I-134 D D I-135 A B I-136 BD I-137 D D I-138 D D I-139 B D I-140 B D I-141 D C I-142 D D I-143 D DI-144 B D I-145 A B B I-146 A D C I-147 D D D I-148 B D D I-149 B DI-150 B C I-151 A B I-152 D D I-153 B D I-154 D D I-155 D D I-156 B DI-157 D D I-158 D D I-159 D D I-160 D D I-161 D D I-162 D D I-163 D DI-164 D D I-165 D D I-166 D D I-167 D D I-168 D D I-169 D D I-170 D DI-171 D D I-172 D D I-173 B D I-174 B D I-175 D D I-176 D D I-177 D DI-178 D D I-179 D D I-180 D D I-181 D D I-182 D D I-183 D D I-184 D DI-185 D D I-186 D D I-187 D D I-188 D D I-189 D D I-190 D D I-191 D DI-192 D D I-193 D D I-194 D I-195 D D I-196 D D I-197 D D I-198 D DI-199 D D I-200 C D I-201 B D I-202 D D I-203 B D I-204 B D I-205 B DI-206 D D I-207 D D I-208 D D I-209 D D I-210 D D I-211 D D I-212 D DI-213 D D I-214 D D I-215 D D I-216 D D I-217 D D I-218 D D I-219 B DI-220 D D I-221 D D I-222 B I-223 D D I-224 D I-225 B D I-226 B C I-227A D I-228 D D I-229 D D I-230 D D I-231 C D I-232 D D I-233 D D I-234 DD I-235 B I-236 B D I-237 A D I-238 B B I-239 B D I-240 B D I-241 D DI-242 B D I-243 B D I-244 D D I-245 D D I-246 D D I-247 D D I-248 D DI-249 D D I-250 B D I-251 D C D I-252 D D I-253 D D I-254 D I-255 A BI-256 B D I-257 B D I-258 D D I-259 A B I-260 B D I-261 D D I-262 D D

1. A compound, wherein the compound is of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R^(A) is

L¹ is a covalent bond or a saturated or unsaturated, straight orbranched, optionally substituted bivalent C₁₋₆ hydrocarbon chain,wherein 0-2 methylene units of L¹ are independently replaced by —O—,—NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—,—S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—; R¹is hydrogen, an optionally substituted C₁₋₆ aliphatic group, or anoptionally substituted cyclic group selected from a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring, a 7-12membered saturated or partially unsaturated bicyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur); R² is hydrogen, an optionally substituted C₁₋₆ aliphaticgroup, —C(O)OR, —C(O)NR₂, or an optionally substituted cyclic groupselected from phenyl and a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur); each instance of R³ is independently hydrogen or anoptionally substituted C₁₋₆ aliphatic group; R⁴ is a cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 7-12 membered saturated or partiallyunsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),and an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),wherein the cyclic group is optionally substituted with one or moreinstances of R⁵; each instance of R⁵ is independently halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, anoptionally substituted C₁₋₆ aliphatic group, or an optionallysubstituted —C₁₋₆ aliphatic-Cy group; L² is a saturated or unsaturated,straight or branched, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 0-2 methylene units of L² are independently replaced by—O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—,—NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or—NRC(O)NR—; R⁶ is an optionally substituted C₁₋₆ aliphatic group, or acyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 7-12 membered saturated orpartially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁷; each instance of R⁷ is independently halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(O)S(O)₂R, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂,—N(R)S(O)₂R, an optionally substituted C₁₋₆ aliphatic group, or Cy, ortwo instances of R⁶ on the same carbon atom are taken together to forman oxo group; L³ is a saturated or unsaturated, straight or branched,optionally substituted bivalent C₁₋₄ hydrocarbon chain, wherein 0-2methylene units of L³ are independently replaced by —O—, —NR—, —S—,—OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—,—NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—; R⁸ is a cyclicgroup selected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, a 7-12 membered saturated or partiallyunsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclicaromatic carbocyclic ring, a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur),and an 8-10 membered bicyclic heteroaromatic ring (having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur),wherein the cyclic group is optionally substituted with one or moreinstances of R⁹; each instance of R⁹ is independently halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, anoptionally substituted C₁₋₆ aliphatic group, an optionally substitutedC₁₋₆ aliphatic-Cy group, or Cy; each Cy is independently an optionallysubstituted cyclic group selected from a 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and a 5-6 membered monocyclic heteroaromatic ring (having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur); and each R is independently hydrogen, or an optionallysubstituted C₁₋₆ aliphatic group, an optionally substituted phenyl, anoptionally substituted 3-7 membered saturated or partially unsaturatedcarbocyclic ring, an optionally substituted 3-7 membered saturated orpartially unsaturated heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), or anoptionally substituted 5-6 membered heteroaryl ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur);or two R groups on the same nitrogen are taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring (having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur); wherein the compound is not5-(2-(6-chloro-1H-indol-3-yl)acetyl)-2-(4-isopropoxy-3-methoxybenzoyl)-N-(1-(methylamino)-1-oxo-5-phenylpentan-2-yl)octahydro-1H-pyrrolo[3,4-c]pyridine-7-carboxamide.2. The compound of claim 1, wherein R^(A) is


3. The compound of claim 1, wherein L¹ is a covalent bond; or wherein L¹is a saturated or unsaturated, straight or branched, optionallysubstituted bivalent C₁₋₆ hydrocarbon chain, wherein 0-2 methylene unitsof L¹ are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —C(S)—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—, or —NRC(O)NR—; or wherein L¹ is anoptionally substituted straight or branched C₁₋₄ alkylene chain, wherein1-2 methylene units of L¹ are independently replaced by —O—, —NR—,—C(O)O—, or —NRC(O)—; or wherein L¹ is

or wherein L¹ is

or wherein L¹ is

4-8. (canceled)
 9. The compound of claim 1, wherein R¹ is hydrogenwherein R¹ is an optionally substituted C₁₋₆ aliphatic group; or whereinR¹ is an optionally substituted cyclic group selected from a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,a 7-12 membered saturated or partially unsaturated bicyclic carbocyclicring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8membered saturated or partially unsaturated monocyclic heterocyclic ring(having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur), a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromaticring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur); or wherein R¹ an optionally substituted cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); or wherein R¹is an optionally substituted cyclic group selected from phenyl,cyclohexyl, cyclopentyl, cycloheptyl, tetrahydrofuranyl,tetrahydropyranyl, indole, and benzotriazole; or wherein R¹ isoptionally substituted cyclohexyl; or wherein R¹ is optionallysubstituted phenyl. 10-15. (canceled)
 16. The compound of claim 1,wherein R² is an optionally substituted C₁₋₆ aliphatic group, —C(O)OR,—C(O)NR₂, or an optionally substituted cyclic group selected from phenyland a 5-6 membered monocyclic heteroaromatic ring (having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur);or wherein R² is C(O)NR₂; or wherein R² is hydrogen, methyl, —C(O)NHCH₃,—C(O)NH₂, —C(O)OCH₃, or —C(O)OH; or wherein R² is a 5-6 memberedmonocyclic heteroaromatic ring (having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur); or wherein R² is anoxazolyl or pyrimidinyl group. 17-20. (canceled)
 21. The compound ofclaim 1, wherein R^(A) is


22. The compound of claim 1, wherein R⁴ is a cyclic group selected froma 3-8 membered saturated or partially unsaturated monocyclicheterocyclic ring (having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), and a 5-6 membered monocyclicheteroaromatic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), wherein the cyclic group is optionallysubstituted with one or more instances of R⁵; or wherein R⁴ is a cyclicgroup selected from phenyl, pyridine, and piperidine, wherein the cyclicgroup is optionally substituted with one or more instances of R⁵. 23.(canceled)
 24. The compound of claim 1, wherein R⁵ is —OR, —C(O)R, anoptionally substituted C₁₋₆ aliphatic group, or an optionallysubstituted —C₁₋₆ aliphatic-Cy group; or wherein R⁵ is an optionallysubstituted benzyl group, an optionally substituted benzoyl group, anoptionally substituted phenoxy group, or an optionally substitutedphenylacetyl group.
 25. (canceled)
 26. The compound of claim 1, whereineach R³ is hydrogen.
 27. The compound of claim 1, wherein R^(A) is asubstituent selected from: TABLE Al

or TABLE A2

or wherein R^(A) is

28-30. (canceled)
 31. The compound of claim 1, wherein L² is asaturated, straight, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 1 methylene unit of L² is replaced by —C(O)—; or whereinL² is —C(O)—.
 32. (canceled)
 33. The compound of claim 1, wherein R⁶ isa cyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, a 7-12 membered saturated orpartially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁷; or wherein R⁶ is a cyclic group selected fromphenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 5-6membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), wherein thecyclic group is optionally substituted with one or more instances of R⁷;or wherein R⁶ is a cyclic group selected from cyclohexyl, phenyl,quinolinyl, isoquinolinyl, quinoxalinyl,2,3-dihydrobenzo[b][1,4]dioxinyl, pyrazolyl, isoxazolyl, imidazolyl,thiazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,2,3-dihydrobenzo[d]furanyl, benzofuranyl, indolyl, benzo[1,2,3]triazole,benzimidazolyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl,indazolyl, indolinyl, indolizinyl, isoindolinyl, and2,3,-dihydrobenzo[d]oxazolyl, wherein the cyclic group is optionallysubstituted with one or more instances of R⁷. 34-35. (canceled)
 36. Thecompound of claim 1, wherein each R⁷ is independently halogen, —CN, —OR,—NR₂, —S(O)₂NR₂, —N(R)C(O)R, —N(R)C(O)S(O)₂R, an optionally substitutedC₁₋₆ aliphatic group, or Cy, or two instances of R⁷ on the same carbonatom are taken together to form an oxo group.
 37. (canceled)
 38. Thecompound of claim 1, wherein —L²—R⁶ is a substituent selected from:TABLE B1

or, TABLE B2

or wherein —L-R⁶ is

39-41. (canceled)
 42. The compound of claim 1, wherein L³ is asaturated, straight, optionally substituted bivalent C₁₋₄ hydrocarbonchain, wherein 1 methylene unit of L³ is replaced by —O—, —NR—, —OC(O)—,—C(O)O—, —C(O)—, —NRC(O)—, or —C(O)NR; or wherein L³ is a saturated,straight, optionally substituted bivalent C₁₋₄ hydrocarbon chain,wherein 1 methylene unit of L³ is replaced by —C(O)—; or wherein L³ is—C(O)CH₂—, —C(O)C(CH₃)H—, —C(O)C(CH₃)₂—, —C(O)CH₂CH₂—, — C(O)CH₂CH₂CH₂—,

or —C(O)—; or wherein L³ is —C(O)CH₂—,

or —C(O)C(CH₃)H—. 43-45. (canceled)
 46. The compound of claim 1, whereinR⁸ is a cyclic group selected from phenyl, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a7-12 membered saturated or partially unsaturated bicyclic heterocyclicring (having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring(having 1-4 heteroatoms independently selected from nitrogen, oxygen,and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur), wherein the cyclic group is optionally substituted with one ormore instances of R⁹ or wherein R⁸ is an 8-10 membered bicyclicheteroaromatic ring (having 1-5 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), optionally substituted with one or moreinstances of R⁹; or wherein R⁸ is a cyclic group selected from indolyl,indazolyl, benzimidazolyl, benzofuranyl, phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrazolyl,tetrazolyl, quinoxalinyl, indolizinyl, thiazolyl, oxazolyl, pyrrolyl,imidazo[1,2-a]pyrazinyl, and tetrahydropyranyl wherein the cyclic groupis optionally substituted with one or more instances of R⁹. 47-48.(canceled)
 49. The compound of claim 1, wherein each instance of R⁹ isindependently halogen, —CN, —OR, or an optionally substituted C₁₋₆aliphatic group; or wherein each instance of R⁹ is independently chloro,bromo, —CN, methyl, or methoxy.
 50. (canceled)
 51. The compound ofanyone of claim 1, wherein —L³—R⁸ is a substituent selected from: TABLEC1

TABLE C2

or, wherein —L³—R⁸ is

52-54. (canceled)
 55. The compound of claim 1, wherein the compound ofFormula I is a compound of any of the following Formulae:

or a pharmaceutically acceptable salt thereof.
 56. The compound of claim1, wherein R^(A) is

L¹ is

R¹ is a C₁₋₄ aliphatic group or an optionally substituted cyclic groupselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, a 3-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring (having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur), a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and an 8-10membered bicyclic heteroaromatic ring (having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); R² ishydrogen, methyl, —C(O)NHCH₃, —C(O)NH₂, —C(O)OCH₃, —C(O)OH, or a 5-6membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur); R⁴ is acyclic group selected from a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring (having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), and a 5-6membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur), wherein thecyclic group is optionally substituted with one or more instances of R⁵;each R⁵ is independently —OR, —C(O)R, an optionally substituted C₁₋₆aliphatic group, or an optionally substituted —C₁₋₆ aliphatic-Cy group;L² is —C(O)—; R⁶ is a cyclic group selected from phenyl, an 8-10membered bicyclic aromatic carbocyclic ring, a 5-6 membered monocyclicheteroaromatic ring (having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), and an 8-10 membered bicyclicheteroaromatic ring (having 1-5 heteroatoms independently selected fromnitrogen, oxygen, and sulfur), wherein the cyclic group is optionallysubstituted with one or more instances of R⁷; each R⁷ is independently—OR, an optionally substituted C₁₋₆ aliphatic group, Cy or two instancesof R⁷ on the same carbon atom are taken together to form an oxo group;L³ is —C(O)CH₂—,

or —C(O)C(CH₃)H—; R⁸ is an 8-10 membered bicyclic heteroaromatic ring(having 1-5 heteroatoms independently selected from nitrogen, oxygen,and sulfur), optionally substituted with one or more instances of R⁹;each instance of R⁹ is independently halogen, —CN, —OR, or a C₁₋₆aliphatic group; and each instance of Cy is independently phenyl or a5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur). 57-62.(canceled)
 63. The compound of claim 1, wherein the compound is one ofthose in Table 1: # Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

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or a pharmaceutically acceptable salt thereof.
 64. A pharmaceuticallyacceptable composition comprising a compound of claim 1, and apharmaceutically acceptable carrier, excipient, vehicle, adjuvant ordiluent; optionally further comprising an additional therapeutic agent.65. (canceled)
 66. A method of inhibiting the activity of acyclin-dependent kinase (CDK) comprising contacting a compound of claim1 with the CDK.
 67. A method of treating a disease or disorderassociated with CDK2 activity in a patient comprising administering tothe patient in need thereof a compound of claim 1, optionally wherein:the disease or disorder associated with CDK2 activity is selected fromcancers, myeloproliferative disorders, autoimmune disorders,inflammatory disorders, viral infections, and fibrotic disorders; or thedisease or disorder associated with CDK2 activity is a cancer; or thedisease or disorder associated with CDK2 activity is a cancer selectedfrom breast cancer, ovarian cancer, bladder cancer, uterine cancer,prostate cancer, lung cancer, esophageal cancer, head and neck cancer,colorectal cancer, kidney cancer, liver cancer, pancreatic cancer,stomach cancer, melanoma and thyroid cancer; or the disease or disorderassociated with CDK2 activity is liver fibrosis; or the disease ordisorder associated with CDK2 activity is Cushing disease; or thedisease or disorder associated with CDK2 activity is polycystic kidneydisease; or the disease or disorder associated with CDK2 activity isAlzheimer's disease. 68-74. (canceled)
 75. A method of reducing malefertility comprising administering to the patient in need thereof acompound of claim 1.